rs11867551

chr17-7727187-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020877.5(DNAH2):c.294T>C(p.His98=) 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:2
• Conservation: PhyloP100: -1.15

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
DNAH2	NM_020877.5	c.294T>C	p.His98=	synonymous_variant	4/86	ENST00000572933.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH2	ENST00000572933.6	c.294T>C	p.His98=	synonymous_variant	4/86	2	NM_020877.5	P1
DNAH2	ENST00000570791.5	c.294T>C	p.His98=	synonymous_variant	4/14	1
DNAH2	ENST00000389173.6	c.294T>C	p.His98=	synonymous_variant	3/85	2		P1

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

GnomAD3 exomes AF: 0.127 AC: 31251 AN: 245628 Hom.: 2358 AF XY: 0.129 AC XY: 17161 AN XY: 133232

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 SAS exome AF: 0.0874

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

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.0613

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.000381

Gnomad4 SAS exome AF: 0.0882

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.173

Gnomad4 OTH exome AF: 0.145

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

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0923

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0933

Gnomad4 FIN AF: 0.170

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.128

Alfa AF: 0.157 Hom.: 3294

Bravo AF: 0.132

Asia WGS AF: 0.0490 AC: 171 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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 -

DNAH2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.078
Dann	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs11867551; hg19: chr17-7630505; COSMIC: COSV50014661;