Genetic Variant HSH2D:p.Cys166Tyr (chr19-16157232-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001382417.1(HSH2D):c.497G>A(p.Cys166Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,560,522 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0061 ( 11 hom., cov: 31)

Exomes 𝑓: 0.00063 ( 12 hom. )

Consequence

HSH2D
NM_001382417.1 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.109

Variant links:

Genes affected

HSH2D (HGNC:24920): (hematopoietic SH2 domain containing) T-cell activation requires 2 signals: recognition of antigen by the T-cell receptor (see TCR; MIM 186880) and a costimulatory signal provided primarily by CD28 (MIM 186760) in naive T cells. HSH2 is a target of both of these signaling pathways (Greene et al., 2003 [PubMed 12960172]).[supplied by OMIM, Mar 2008]

HSH2D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037470162).

BP6

Variant 19-16157232-G-A is Benign according to our data. Variant chr19-16157232-G-A is described in ClinVar as [Benign]. Clinvar id is 775578.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00609 (926/152160) while in subpopulation AFR AF= 0.0216 (896/41498). AF 95% confidence interval is 0.0204. There are 11 homozygotes in gnomad4. There are 435 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSH2D	NM_001382417.1 link	c.497G>A	p.Cys166Tyr	missense_variant	Exon 6 of 6	ENST00000613986.4	NP_001369346.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSH2D	ENST00000613986.4 link	c.497G>A	p.Cys166Tyr	missense_variant	Exon 6 of 6	2	NM_001382417.1	ENSP00000483354.1		Q96JZ2-1

Frequencies

GnomAD3 genomes

AF:

0.00606

AC:

922

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00164

AC:

333

AN:

202722

Hom.:

AF XY:

0.00118

AC XY:

128

AN XY:

108930

show subpopulations

Gnomad AFR exome

AF:

0.0206

Gnomad AMR exome

AF:

0.000836

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000485

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000639

GnomAD4 exome

AF:

0.000629

AC:

886

AN:

1408362

Hom.:

Cov.:

AF XY:

0.000543

AC XY:

378

AN XY:

696556

show subpopulations

Gnomad4 AFR exome

AF:

0.0233

Gnomad4 AMR exome

AF:

0.000960

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000782

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000919

Gnomad4 OTH exome

AF:

0.00178

GnomAD4 genome

AF:

0.00609

AC:

926

AN:

152160

Hom.:

Cov.:

AF XY:

0.00585

AC XY:

435

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0216

Gnomad4 AMR

AF:

0.00138

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.00756

ESP6500AA

AF:

0.0181

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00164

AC:

198

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.81

CADD

Benign

7.4

DANN

Benign

0.46

DEOGEN2

Benign

0.061

T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.36

.;T;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;N;.

PrimateAI

Benign

0.24

Sift4G

Benign

0.41

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.047

MVP

0.030

ClinPred

0.000094

GERP RS

-0.96

Varity_R

0.075

gMVP

0.17

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

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