rs62441683

chr7-21588624-C-Gchr7-21588624-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/17 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:6
• Conservation: PhyloP100: 1.78

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 163098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21588624-C-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.1961C>G	p.Ser654Cys	missense_variant	11/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.1961C>G	p.Ser654Cys	missense_variant	11/82	5	NM_001277115.2	P1

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

GnomAD3 exomes AF: 0.124 AC: 30803 AN: 248726 Hom.: 2298 AF XY: 0.129 AC XY: 17447 AN XY: 134928

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 SAS exome AF: 0.114

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

Gnomad4 AFR exome AF: 0.0234

Gnomad4 AMR exome AF: 0.0803

Gnomad4 ASJ exome AF: 0.181

Gnomad4 EAS exome AF: 0.0241

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.143

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

Gnomad4 AFR AF: 0.0292

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.0344

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.137

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Primary ciliary dyskinesia 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2019

- -

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
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
MutationTaster	Benign	0.88	P
PrimateAI	Benign	0.32	T
Polyphen		0.96	.;.;D
Vest4		0.15
ClinPred		0.022	T
GERP RS		3.7
Varity_R		0.16
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs62441683; hg19: chr7-21628242;