rs117035657

chr17-7733179-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020877.5(DNAH2):c.492G>A(p.Arg164=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,614,168 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (10 hom., cov: 31)
  • Exomes 𝑓: 0.011 (125 hom.)
• Consequence: DNAH2 NM_020877.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0810

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=-0.72).
• BP6: Variant 17-7733179-G-A is Benign according to our data. Variant chr17-7733179-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 402716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.081 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00843 (1284/152286) while in subpopulation NFE AF= 0.0127 (863/68014). AF 95% confidence interval is 0.012. There are 10 homozygotes in gnomad4. There are 609 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH2	NM_020877.5	c.492G>A	p.Arg164=	synonymous_variant	5/86	ENST00000572933.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH2	ENST00000572933.6	c.492G>A	p.Arg164=	synonymous_variant	5/86	2	NM_020877.5	P1
DNAH2	ENST00000570791.5	c.492G>A	p.Arg164=	synonymous_variant	5/14	1
DNAH2	ENST00000389173.6	c.492G>A	p.Arg164=	synonymous_variant	4/85	2		P1

Frequencies

GnomAD3 genomes AF: 0.00844 AC: 1285 AN: 152168 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0103 AC: 2599 AN: 251448 Hom.: 27 AF XY: 0.0100 AC XY: 1361 AN XY: 135902

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.00880

GnomAD4 exome AF: 0.0112 AC: 16367 AN: 1461882 Hom.: 125 Cov.: 31 AF XY: 0.0107 AC XY: 7807 AN XY: 727244

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.00318

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0220

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.00932

GnomAD4 genome AF: 0.00843 AC: 1284 AN: 152286 Hom.: 10 Cov.: 31 AF XY: 0.00818 AC XY: 609 AN XY: 74472

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0185

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00963 Hom.: 6

Bravo AF: 0.00716

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely 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: Frequency, silent variant not near splice site -

DNAH2-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 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	-0.72
Cadd	Benign	4.1
Dann	Benign	0.58

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: rs117035657; hg19: chr17-7636497; COSMIC: COSV50019961;