17-7819047-C-T

Variant names:

• chr17-7819047-C-T
• rs7213894
• NM_020877.5:c.10799C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020877.5(DNAH2):​c.10799C>T​(p.Thr3600Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 1,605,244 control chromosomes in the GnomAD database, including 287,476 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T3600T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.63 (31171 hom., cov: 29)
  • Exomes 𝑓: 0.59 (256305 hom.)
• Consequence: DNAH2 NM_020877.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.93
• Publications: 47 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0320699E-6).
• BP6: Variant 17-7819047-C-T is Benign according to our data. Variant chr17-7819047-C-T is described in ClinVar as Benign. ClinVar VariationId is 402713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH2	NM_020877.5	c.10799C>T	p.Thr3600Ile	missense_variant	Exon 71 of 86	ENST00000572933.6	NP_065928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH2	ENST00000572933.6	c.10799C>T	p.Thr3600Ile	missense_variant	Exon 71 of 86	2	NM_020877.5	ENSP00000458355.1
DNAH2	ENST00000389173.6	c.10799C>T	p.Thr3600Ile	missense_variant	Exon 70 of 85	2		ENSP00000373825.2
DNAH2	ENST00000575105.1	c.1646C>T	p.Thr549Ile	missense_variant	Exon 12 of 23	5		ENSP00000461726.1

Frequencies

GnomAD3 genomes AF: 0.633 AC: 95974 AN: 151584 Hom.: 31120 Cov.: 29

Gnomad AFR AF: 0.754

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.648

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.679

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.639

GnomAD2 exomes AF: 0.591 AC: 142873 AN: 241768 AF XY: 0.601

Gnomad AFR exome AF: 0.760

Gnomad AMR exome AF: 0.505

Gnomad ASJ exome AF: 0.650

Gnomad EAS exome AF: 0.334

Gnomad FIN exome AF: 0.608

Gnomad NFE exome AF: 0.599

Gnomad OTH exome AF: 0.605

GnomAD4 exome AF: 0.591 AC: 858769 AN: 1453542 Hom.: 256305 Cov.: 74 AF XY: 0.596 AC XY: 431025 AN XY: 723062

African (AFR) AF: 0.760 AC: 25393 AN: 33416

American (AMR) AF: 0.516 AC: 22925 AN: 44404

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 16909 AN: 26092

East Asian (EAS) AF: 0.372 AC: 14729 AN: 39576

South Asian (SAS) AF: 0.693 AC: 59609 AN: 86036

European-Finnish (FIN) AF: 0.603 AC: 28618 AN: 47484

Middle Eastern (MID) AF: 0.770 AC: 4236 AN: 5498

European-Non Finnish (NFE) AF: 0.585 AC: 650276 AN: 1110810

Other (OTH) AF: 0.599 AC: 36074 AN: 60226

GnomAD4 genome AF: 0.633 AC: 96084 AN: 151702 Hom.: 31171 Cov.: 29 AF XY: 0.631 AC XY: 46790 AN XY: 74116

African (AFR) AF: 0.755 AC: 31212 AN: 41352

American (AMR) AF: 0.578 AC: 8825 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 2251 AN: 3472

East Asian (EAS) AF: 0.349 AC: 1782 AN: 5100

South Asian (SAS) AF: 0.679 AC: 3247 AN: 4782

European-Finnish (FIN) AF: 0.604 AC: 6380 AN: 10570

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.591 AC: 40113 AN: 67844

Other (OTH) AF: 0.642 AC: 1356 AN: 2112

Alfa AF: 0.604 Hom.: 91929

Bravo AF: 0.631

TwinsUK AF: 0.581 AC: 2155

ALSPAC AF: 0.579 AC: 2231

ESP6500AA AF: 0.751 AC: 3311

ESP6500EA AF: 0.598 AC: 5141

ExAC AF: 0.598 AC: 72537

Asia WGS AF: 0.563 AC: 1958 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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: Frequency -

DNAH2-related disorder Benign:1

Oct 17, 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 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
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.13
DEOGEN2	Benign	0.059	T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.58	.;T;T
MetaRNN	Benign	0.0000010	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.7	N;N;.
PhyloP100		2.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	4.8	.;N;.
REVEL	Benign	0.26
Sift	Benign	1.0	.;T;.
Sift4G	Benign	1.0	.;.;T
Polyphen		0.0	B;B;.
Vest4		0.21
MPC		0.29
ClinPred		0.0030	T
GERP RS		4.1
Varity_R		0.055
gMVP		0.27
Mutation Taster		=95/5	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: rs7213894; hg19: chr17-7722365; COSMIC: COSV66716988;