chr7-21588624-C-G

Variant names:

• chr7-21588624-C-G
• rs62441683
• NM_001277115.2:c.1961C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001277115.2(DNAH11):​c.1961C>G​(p.Ser654Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,609,436 control chromosomes in the GnomAD database, including 19,431 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S654F) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1279 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18152 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.78
• Publications: 18 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017820597).
• BP6: Variant 7-21588624-C-G is Benign according to our data. Variant chr7-21588624-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.1961C>G	p.Ser654Cys	missense_variant	Exon 11 of 82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.1961C>G	p.Ser654Cys	missense_variant	Exon 11 of 82	5	NM_001277115.2	ENSP00000475939.1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17357 AN: 152108 Hom.: 1279 Cov.: 32

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.0343

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.140

GnomAD2 exomes AF: 0.124 AC: 30803 AN: 248726 AF XY: 0.129

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.0751

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.0309

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.152 AC: 220923 AN: 1457210 Hom.: 18152 Cov.: 33 AF XY: 0.151 AC XY: 109822 AN XY: 725084

African (AFR) AF: 0.0234 AC: 781 AN: 33442

American (AMR) AF: 0.0803 AC: 3590 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4714 AN: 26082

East Asian (EAS) AF: 0.0241 AC: 955 AN: 39664

South Asian (SAS) AF: 0.115 AC: 9926 AN: 86170

European-Finnish (FIN) AF: 0.121 AC: 6452 AN: 53292

Middle Eastern (MID) AF: 0.187 AC: 1074 AN: 5754

European-Non Finnish (NFE) AF: 0.167 AC: 184813 AN: 1107904

Other (OTH) AF: 0.143 AC: 8618 AN: 60212

GnomAD4 genome AF: 0.114 AC: 17355 AN: 152226 Hom.: 1279 Cov.: 32 AF XY: 0.111 AC XY: 8294 AN XY: 74426

African (AFR) AF: 0.0292 AC: 1212 AN: 41554

American (AMR) AF: 0.114 AC: 1738 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 648 AN: 3472

East Asian (EAS) AF: 0.0344 AC: 178 AN: 5172

South Asian (SAS) AF: 0.107 AC: 514 AN: 4812

European-Finnish (FIN) AF: 0.126 AC: 1333 AN: 10598

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11354 AN: 68008

Other (OTH) AF: 0.137 AC: 289 AN: 2114

Alfa AF: 0.154 Hom.: 1513

Bravo AF: 0.110

TwinsUK AF: 0.182 AC: 675

ALSPAC AF: 0.164 AC: 633

ESP6500AA AF: 0.0270 AC: 101

ESP6500EA AF: 0.168 AC: 1378

ExAC AF: 0.125 AC: 15090

Asia WGS AF: 0.0520 AC: 183 AN: 3478

EpiCase AF: 0.174

EpiControl AF: 0.175

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ser654Cys in exon 11 of DNAH11: This variant is not expected to have clinical si gnificance because it has been identified in 16.8% (1378/8220) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs62441683). -

Primary ciliary dyskinesia Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Primary ciliary dyskinesia 7 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.66
DEOGEN2	Benign	0.14	.;.;T
Eigen	Benign	0.089
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.69	T;T;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;.;L
PhyloP100		1.8
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.4	.;N;.
REVEL	Benign	0.26
Sift	Benign	0.14	.;T;.
Polyphen		0.96	.;.;D
Vest4		0.15
ClinPred		0.022	T
GERP RS		3.7
Varity_R		0.16
gMVP		0.12
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs62441683; hg19: chr7-21628242;