rs11867551

Variant names:

• chr17-7727187-T-C
• rs11867551
• NM_020877.5:c.294T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020877.5(DNAH2):​c.294T>C​(p.His98His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,607,788 control chromosomes in the GnomAD database, including 20,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1646 hom., cov: 31)
  • Exomes 𝑓: 0.16 (19111 hom.)
• Consequence: DNAH2 NM_020877.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.15
• Publications: 15 publications found

Genes affected

DNAH2 (HGNC:2948): (dynein axonemal heavy chain 2) Dyneins are microtubule-associated motor protein complexes composed of several heavy, light, and intermediate chains. The axonemal dyneins, found in cilia and flagella, are components of the outer and inner dynein arms attached to the peripheral microtubule doublets. DNAH2 is an axonemal inner arm dynein heavy chain (Chapelin et al., 1997 [PubMed 9256245]).[supplied by OMIM, Mar 2008]

DNAH2 Gene-Disease associations (from GenCC):

• spermatogenic failure 45

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 17-7727187-T-C is Benign according to our data. Variant chr17-7727187-T-C is described in ClinVar as Benign. ClinVar VariationId is 402705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH2	NM_020877.5	c.294T>C	p.His98His	synonymous_variant	Exon 4 of 86	ENST00000572933.6	NP_065928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH2	ENST00000572933.6	c.294T>C	p.His98His	synonymous_variant	Exon 4 of 86	2	NM_020877.5	ENSP00000458355.1
DNAH2	ENST00000570791.5	c.294T>C	p.His98His	synonymous_variant	Exon 4 of 14	1		ENSP00000460245.1
DNAH2	ENST00000389173.6	c.294T>C	p.His98His	synonymous_variant	Exon 3 of 85	2		ENSP00000373825.2

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21064 AN: 152050 Hom.: 1642 Cov.: 31

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.0924

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0922

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.127 AC: 31251 AN: 245628 AF XY: 0.129

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.0566

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.000279

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.157 AC: 228567 AN: 1455620 Hom.: 19111 Cov.: 32 AF XY: 0.155 AC XY: 112073 AN XY: 724248

African (AFR) AF: 0.113 AC: 3731 AN: 33098

American (AMR) AF: 0.0613 AC: 2648 AN: 43200

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 4002 AN: 25870

East Asian (EAS) AF: 0.000381 AC: 15 AN: 39412

South Asian (SAS) AF: 0.0882 AC: 7511 AN: 85172

European-Finnish (FIN) AF: 0.173 AC: 9233 AN: 53348

Middle Eastern (MID) AF: 0.107 AC: 613 AN: 5748

European-Non Finnish (NFE) AF: 0.173 AC: 192064 AN: 1109632

Other (OTH) AF: 0.145 AC: 8750 AN: 60140

GnomAD4 genome AF: 0.139 AC: 21089 AN: 152168 Hom.: 1646 Cov.: 31 AF XY: 0.136 AC XY: 10109 AN XY: 74384

African (AFR) AF: 0.116 AC: 4803 AN: 41526

American (AMR) AF: 0.0923 AC: 1410 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 532 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.0933 AC: 450 AN: 4822

European-Finnish (FIN) AF: 0.170 AC: 1806 AN: 10596

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11522 AN: 67982

Other (OTH) AF: 0.128 AC: 271 AN: 2112

Alfa AF: 0.155 Hom.: 3891

Bravo AF: 0.132

Asia WGS AF: 0.0490 AC: 171 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DNAH2-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.078
DANN	Benign	0.39
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs11867551; hg19: chr17-7630505; COSMIC: COSV50014661;