rs62059684

chr17-7776841-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020877.5(DNAH2):c.5010G>A(p.Ala1670=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,612,050 control chromosomes in the GnomAD database, including 77,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5309 hom., cov: 31)
  • Exomes 𝑓: 0.30 (72385 hom.)
• Consequence: DNAH2 NM_020877.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.137

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 17-7776841-G-A is Benign according to our data. Variant chr17-7776841-G-A is described in ClinVar as [Benign]. Clinvar id is 402708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.137 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH2	NM_020877.5	c.5010G>A	p.Ala1670=	synonymous_variant	32/86	ENST00000572933.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH2	ENST00000572933.6	c.5010G>A	p.Ala1670=	synonymous_variant	32/86	2	NM_020877.5	P1
DNAH2	ENST00000389173.6	c.5010G>A	p.Ala1670=	synonymous_variant	31/85	2		P1
DNAH2	ENST00000574518.1	c.*1386G>A		3_prime_UTR_variant, NMD_transcript_variant	13/22	2

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34718 AN: 151948 Hom.: 5311 Cov.: 31

Gnomad AFR AF: 0.0571

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.236

GnomAD3 exomes AF: 0.241 AC: 60310 AN: 250516 Hom.: 9219 AF XY: 0.245 AC XY: 33249 AN XY: 135440

Gnomad AFR exome AF: 0.0519

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.330

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.132

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.278

GnomAD4 exome AF: 0.302 AC: 440227 AN: 1459984 Hom.: 72385 Cov.: 35 AF XY: 0.299 AC XY: 216983 AN XY: 726284

Gnomad4 AFR exome AF: 0.0460

Gnomad4 AMR exome AF: 0.148

Gnomad4 ASJ exome AF: 0.334

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.135

Gnomad4 FIN exome AF: 0.347

Gnomad4 NFE exome AF: 0.338

Gnomad4 OTH exome AF: 0.270

GnomAD4 genome AF: 0.228 AC: 34713 AN: 152066 Hom.: 5309 Cov.: 31 AF XY: 0.225 AC XY: 16687 AN XY: 74320

Gnomad4 AFR AF: 0.0569

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.335

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.349

Gnomad4 NFE AF: 0.340

Gnomad4 OTH AF: 0.233

Alfa AF: 0.303 Hom.: 4196

Bravo AF: 0.209

Asia WGS AF: 0.0540 AC: 189 AN: 3478

EpiCase AF: 0.335

EpiControl AF: 0.335

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: Frequency -

DNAH2-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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	-0.38
Cadd	Benign	1.3
Dann	Benign	0.83

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: rs62059684; hg19: chr17-7680159; COSMIC: COSV66719577;