17-7832924-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020877.5(DNAH2):c.12974C>G(p.Pro4325Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0316 in 1,614,136 control chromosomes in the GnomAD database, including 911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 66 hom., cov: 32)

Exomes 𝑓: 0.032 ( 845 hom. )

Consequence

DNAH2
NM_020877.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 6.60

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

spermatogenic failure 45
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

DNAH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008742511).

BP6

Variant 17-7832924-C-G is Benign according to our data. Variant chr17-7832924-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 402718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0248 (3769/152264) while in subpopulation NFE AF = 0.0375 (2551/68012). AF 95% confidence interval is 0.0363. There are 66 homozygotes in GnomAd4. There are 1747 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH2	NM_020877.5 link	c.12974C>G	p.Pro4325Arg	missense_variant	Exon 84 of 86	ENST00000572933.6	NP_065928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH2	ENST00000572933.6 link	c.12974C>G	p.Pro4325Arg	missense_variant	Exon 84 of 86	2	NM_020877.5	ENSP00000458355.1
DNAH2	ENST00000389173.6 link	c.12974C>G	p.Pro4325Arg	missense_variant	Exon 83 of 85	2		ENSP00000373825.2

Frequencies

GnomAD3 genomes

AF:

0.0248

AC:

3770

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00705

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0244

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0327

Gnomad FIN

AF:

0.0206

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0375

Gnomad OTH

AF:

0.0234

GnomAD2 exomes

AF:

0.0269

AC:

6760

AN:

251458

AF XY:

0.0288

show subpopulations

Gnomad AFR exome

AF:

0.00566

Gnomad AMR exome

AF:

0.0162

Gnomad ASJ exome

AF:

0.0245

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0228

Gnomad NFE exome

AF:

0.0365

Gnomad OTH exome

AF:

0.0276

GnomAD4 exome

AF:

0.0323

AC:

47225

AN:

1461872

Hom.:

845

Cov.:

AF XY:

0.0327

AC XY:

23792

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00439

AC:

147

AN:

33478

American (AMR)

AF:

0.0169

AC:

756

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0268

AC:

700

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0337

AC:

2907

AN:

86258

European-Finnish (FIN)

AF:

0.0212

AC:

1131

AN:

53412

Middle Eastern (MID)

AF:

0.0251

AC:

145

AN:

5768

European-Non Finnish (NFE)

AF:

0.0356

AC:

39538

AN:

1112000

Other (OTH)

AF:

0.0314

AC:

1897

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

2896

5792

8689

11585

14481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1442

2884

4326

5768

7210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0248

AC:

3769

AN:

152264

Hom.:

Cov.:

AF XY:

0.0235

AC XY:

1747

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00703

AC:

292

AN:

41548

American (AMR)

AF:

0.0243

AC:

372

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.0329

AC:

159

AN:

4828

European-Finnish (FIN)

AF:

0.0206

AC:

218

AN:

10606

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0375

AC:

2551

AN:

68012

Other (OTH)

AF:

0.0237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

202

404

606

808

1010

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0259

Hom.:

Bravo

AF:

0.0228

TwinsUK

AF:

0.0299

AC:

111

ALSPAC

AF:

0.0317

AC:

122

ESP6500AA

AF:

0.00726

AC:

ESP6500EA

AF:

0.0384

AC:

330

ExAC

AF:

0.0277

AC:

3357

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.0393

EpiControl

AF:

0.0370

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely 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 -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;T

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

.;D

MetaRNN

Benign

0.0087

T;T

MetaSVM

Benign

-0.46

MutationAssessor

Pathogenic

4.5

H;H

PhyloP100

6.6

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-7.5

.;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0060

.;D

Polyphen

1.0

D;D

Vest4

0.47

MPC

0.97

ClinPred

0.057

GERP RS

4.5

Varity_R

0.83

gMVP

0.85

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over