rs7213894

Positions:

chr17-7819047-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.63 ( 31171 hom., cov: 29)

Exomes 𝑓: 0.59 ( 256305 hom. )

Consequence

DNAH2
NM_020877.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.93

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNAH2. . Gene score misZ 1.883 (greater than the threshold 3.09). Trascript score misZ 4.8003 (greater than threshold 3.09). GenCC has associacion of gene with spermatogenic failure 45.

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 id 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/exons	MANE	Protein	UniProt
DNAH2	NM_020877.5 linkuse as main transcript	c.10799C>T	p.Thr3600Ile	missense_variant	71/86	ENST00000572933.6	NP_065928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH2	ENST00000572933.6 linkuse as main transcript	c.10799C>T	p.Thr3600Ile	missense_variant	71/86	2	NM_020877.5	ENSP00000458355	P1	Q9P225-1
DNAH2	ENST00000389173.6 linkuse as main transcript	c.10799C>T	p.Thr3600Ile	missense_variant	70/85	2		ENSP00000373825	P1	Q9P225-1
DNAH2	ENST00000575105.1 linkuse as main transcript	c.1646C>T	p.Thr549Ile	missense_variant	12/23	5		ENSP00000461726

Frequencies

GnomAD3 genomes

AF:

0.633

AC:

95974

AN:

151584

Hom.:

31120

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.591

AC:

142873

AN:

241768

Hom.:

43278

AF XY:

0.601

AC XY:

78809

AN XY:

131166

show subpopulations

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 SAS exome

AF:

0.693

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.:

AF XY:

0.596

AC XY:

431025

AN XY:

723062

show subpopulations

Gnomad4 AFR exome

AF:

0.760

Gnomad4 AMR exome

AF:

0.516

Gnomad4 ASJ exome

AF:

0.648

Gnomad4 EAS exome

AF:

0.372

Gnomad4 SAS exome

AF:

0.693

Gnomad4 FIN exome

AF:

0.603

Gnomad4 NFE exome

AF:

0.585

Gnomad4 OTH exome

AF:

0.599

GnomAD4 genome

AF:

0.633

AC:

96084

AN:

151702

Hom.:

31171

Cov.:

AF XY:

0.631

AC XY:

46790

AN XY:

74116

show subpopulations

Gnomad4 AFR

AF:

0.755

Gnomad4 AMR

AF:

0.578

Gnomad4 ASJ

AF:

0.648

Gnomad4 EAS

AF:

0.349

Gnomad4 SAS

AF:

0.679

Gnomad4 FIN

AF:

0.604

Gnomad4 NFE

AF:

0.591

Gnomad4 OTH

AF:

0.642

Alfa

AF:

0.607

Hom.:

44073

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

LINK: link

Submissions by phenotype

DNAH2-related disorder

Benign:1

Benign, no assertion criteria provided

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). -

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 -

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

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.13

DEOGEN2

Benign

0.059

T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.58

.;T;T

MetaRNN

Benign

0.0000010

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-3.7

N;N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.59

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

GERP RS

4.1

Varity_R

0.055

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over