17-7770604-A-T

Position:

• chr17-7770604-A-T

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.4146A>T​(p.Ile1382Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0313 in 1,614,008 control chromosomes in the GnomAD database, including 1,240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (277 hom., cov: 32)
  • Exomes 𝑓: 0.029 (963 hom.)
• Consequence: DNAH2 NM_020877.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.573

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=-0.79).
• BP6: Variant 17-7770604-A-T is Benign according to our data. Variant chr17-7770604-A-T is described in ClinVar as [Benign]. Clinvar id is 402706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.573 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0983 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH2	NM_020877.5	c.4146A>T	p.Ile1382Ile	synonymous_variant	26/86	ENST00000572933.6	NP_065928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH2	ENST00000572933.6	c.4146A>T	p.Ile1382Ile	synonymous_variant	26/86	2	NM_020877.5	ENSP00000458355.1
DNAH2	ENST00000389173.6	c.4146A>T	p.Ile1382Ile	synonymous_variant	25/85	2		ENSP00000373825.2
DNAH2	ENST00000574518.1	n.*409A>T		non_coding_transcript_exon_variant	8/22	2		ENSP00000461273.1
DNAH2	ENST00000574518.1	n.*409A>T		3_prime_UTR_variant	8/22	2		ENSP00000461273.1

Frequencies

GnomAD3 genomes AF: 0.0489 AC: 7443 AN: 152102 Hom.: 274 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0338

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0524

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0517

GnomAD3 exomes AF: 0.0341 AC: 8567 AN: 251438 Hom.: 249 AF XY: 0.0342 AC XY: 4652 AN XY: 135898

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.0714

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0488

Gnomad FIN exome AF: 0.0235

Gnomad NFE exome AF: 0.0289

Gnomad OTH exome AF: 0.0360

GnomAD4 exome AF: 0.0294 AC: 42981 AN: 1461788 Hom.: 963 Cov.: 32 AF XY: 0.0302 AC XY: 21986 AN XY: 727196

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.0199

Gnomad4 ASJ exome AF: 0.0696

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0495

Gnomad4 FIN exome AF: 0.0251

Gnomad4 NFE exome AF: 0.0257

Gnomad4 OTH exome AF: 0.0344

GnomAD4 genome AF: 0.0490 AC: 7465 AN: 152220 Hom.: 277 Cov.: 32 AF XY: 0.0489 AC XY: 3642 AN XY: 74446

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0337

Gnomad4 ASJ AF: 0.0709

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0523

Gnomad4 FIN AF: 0.0263

Gnomad4 NFE AF: 0.0270

Gnomad4 OTH AF: 0.0511

Alfa AF: 0.0279 Hom.: 24

Bravo AF: 0.0509

Asia WGS AF: 0.0370 AC: 127 AN: 3478

EpiCase AF: 0.0352

EpiControl AF: 0.0367

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2020

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 provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.4
DANN	Benign	0.78

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: rs9910089; hg19: chr17-7673922;