chr7-21705497-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_001277115.2(DNAH11):c.6506C>T(p.Ser2169Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2169T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 2.36

Publications

1 publications found

Variant links:

Genes affected

DNAH11 (HGNC:2942): (dynein axonemal heavy chain 11) This gene encodes a ciliary outer dynein arm protein and is a member of the dynein heavy chain family. It is a microtubule-dependent motor ATPase and has been reported to be involved in the movement of respiratory cilia. Mutations in this gene have been implicated in causing Kartagener Syndrome (a combination of situs inversus totalis and Primary Ciliary Dyskinesia (PCD), also called Immotile Cilia Syndrome 1 (ICS1)) and male sterility. [provided by RefSeq, Mar 2013]

DNAH11 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 7
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAH11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP5

Variant 7-21705497-C-T is Pathogenic according to our data. Variant chr7-21705497-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 658037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH11	NM_001277115.2 link	c.6506C>T	p.Ser2169Leu	missense_variant	Exon 39 of 82	ENST00000409508.8	NP_001264044.1	Q96DT5Q96NT7H9NAJ8H9NAJ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8 link	c.6506C>T	p.Ser2169Leu	missense_variant	Exon 39 of 82	5	NM_001277115.2	ENSP00000475939.1		Q96DT5

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000683

AC:

AN:

249062

AF XY:

0.0000592

show subpopulations

Gnomad AFR exome

AF:

0.000711

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461370

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726950

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33462

American (AMR)

AF:

0.0000895

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1111668

Other (OTH)

AF:

0.0000331

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000158

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41540

American (AMR)

AF:

0.000131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000219

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.000257

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000993

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Pathogenic:2Uncertain:1

Dec 13, 2018

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2169 of the DNAH11 protein (p.Ser2169Leu). This variant is present in population databases (rs373946181, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of primary ciliary dyskinesia (PMID: 29467202; internal data). ClinVar contains an entry for this variant (Variation ID: 658037). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNAH11 protein function. For these reasons, this variant has been classified as Pathogenic. -

Jun 14, 2022

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S2169L variant (also known as c.6506C>T), located in coding exon 39 of the DNAH11 gene, results from a C to T substitution at nucleotide position 6506. The serine at codon 2169 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in the homozygous state, and in conjunction with a pathogenic DNAH11 mutation, in multiple unrelated individuals with primary ciliary dyskinesia (Shoemark A et al. Eur Respir J, 2018 02;51:; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Primary ciliary dyskinesia 7

Pathogenic:2

Apr 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DNAH11 c.6506C>T (p.Ser2169Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 249062 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DNAH11 causing Primary Ciliary Dyskinesia 7, allowing no conclusion about variant significance. c.6506C>T has been reported in the homozygous and presumed compound heterozygous state in the literature and at Labcorp in multiple individuals affected with Primary Ciliary Dyskinesia 7 (e.g., Shoemark_2018, internal data). A further affected individual with primary ciliary dyskinesia with a biallelic genotype has been reported by another laboratory, however the details of that case were not available (Ambry Genetics, ClinVar). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29467202). ClinVar contains an entry for this variant (Variation ID: 658037). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Apr 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

.;.;D

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Benign

0.056

MetaRNN

Uncertain

0.57

D;D;D

MetaSVM

Benign

-0.45

PhyloP100

2.4

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.1

.;D;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

.;D;.

Vest4

0.81

MVP

0.54

ClinPred

0.85

GERP RS

3.6

Varity_R

0.75

gMVP

0.75

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over