rs118057786

Positions:

chr17-7759801-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_020877.5(DNAH2):c.2648C>T(p.Ser883Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0123 in 1,614,182 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 12 hom., cov: 32)

Exomes 𝑓: 0.013 ( 164 hom. )

Consequence

DNAH2
NM_020877.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.85

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=0.017301321).

BP6

Variant 17-7759801-C-T is Benign according to our data. Variant chr17-7759801-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 402717.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 = 0.00875 (1333/152340) while in subpopulation NFE AF= 0.0148 (1004/68020). AF 95% confidence interval is 0.014. There are 12 homozygotes in gnomad4. There are 633 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH2	NM_020877.5 linkuse as main transcript	c.2648C>T	p.Ser883Leu	missense_variant	17/86	ENST00000572933.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH2	ENST00000572933.6 linkuse as main transcript	c.2648C>T	p.Ser883Leu	missense_variant	17/86	2	NM_020877.5	P1	Q9P225-1
DNAH2	ENST00000389173.6 linkuse as main transcript	c.2648C>T	p.Ser883Leu	missense_variant	16/85	2		P1	Q9P225-1

Frequencies

GnomAD3 genomes

AF:

0.00876

AC:

1334

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00674

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00838

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.00907

GnomAD3 exomes

AF:

0.00821

AC:

2063

AN:

251396

Hom.:

AF XY:

0.00843

AC XY:

1146

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.00454

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00421

Gnomad FIN exome

AF:

0.00925

Gnomad NFE exome

AF:

0.0131

Gnomad OTH exome

AF:

0.00897

GnomAD4 exome

AF:

0.0126

AC:

18484

AN:

1461842

Hom.:

164

Cov.:

AF XY:

0.0125

AC XY:

9120

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00173

Gnomad4 AMR exome

AF:

0.00432

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00450

Gnomad4 FIN exome

AF:

0.0104

Gnomad4 NFE exome

AF:

0.0149

Gnomad4 OTH exome

AF:

0.0113

GnomAD4 genome

AF:

0.00875

AC:

1333

AN:

152340

Hom.:

Cov.:

AF XY:

0.00850

AC XY:

633

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00224

Gnomad4 AMR

AF:

0.00673

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00838

Gnomad4 NFE

AF:

0.0148

Gnomad4 OTH

AF:

0.00898

Alfa

AF:

0.0128

Hom.:

Bravo

AF:

0.00855

TwinsUK

AF:

0.0170

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0135

AC:

116

ExAC

AF:

0.00843

AC:

1023

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0129

EpiControl

AF:

0.0120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DNAH2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

not specified

Benign:1

Likely 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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as likely 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

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

.;D

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.2

.;D

REVEL

Benign

0.15

Sift

Benign

0.15

.;T

Polyphen

0.67

P;P

Vest4

0.79

MVP

0.42

MPC

0.64

ClinPred

0.014

GERP RS

5.7

Varity_R

0.25

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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