Genetic Variant HAVCR2:p.Arg140Pro (chr5-157104725-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032782.5(HAVCR2):c.419G>C(p.Arg140Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R140L) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HAVCR2
NM_032782.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.202

Publications

73 publications found

Variant links:

Genes affected

HAVCR2 (HGNC:18437): (hepatitis A virus cellular receptor 2) The protein encoded by this gene belongs to the immunoglobulin superfamily, and TIM family of proteins. CD4-positive T helper lymphocytes can be divided into types 1 (Th1) and 2 (Th2) on the basis of their cytokine secretion patterns. Th1 cells are involved in cell-mediated immunity to intracellular pathogens and delayed-type hypersensitivity reactions, whereas, Th2 cells are involved in the control of extracellular helminthic infections and the promotion of atopic and allergic diseases. This protein is a Th1-specific cell surface protein that regulates macrophage activation, and inhibits Th1-mediated auto- and alloimmune responses, and promotes immunological tolerance. [provided by RefSeq, Sep 2011]

HAVCR2 Gene-Disease associations (from GenCC):

subcutaneous panniculitis-like T-cell lymphoma
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

HAVCR2 links:

ENSG00000254246 (HGNC:):

ENSG00000254246 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.029742062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAVCR2	NM_032782.5 link	c.419G>C	p.Arg140Pro	missense_variant	Exon 3 of 7	ENST00000307851.9	NP_116171.3	Q8TDQ0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAVCR2	ENST00000307851.9 link	c.419G>C	p.Arg140Pro	missense_variant	Exon 3 of 7	1	NM_032782.5	ENSP00000312002.4		Q8TDQ0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1450186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720120

African (AFR)

AF:

0.00

AC:

AN:

33356

American (AMR)

AF:

0.00

AC:

AN:

43448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25704

East Asian (EAS)

AF:

0.00

AC:

AN:

39588

South Asian (SAS)

AF:

0.00

AC:

AN:

84184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52754

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105472

Other (OTH)

AF:

0.00

AC:

AN:

59940

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

1.5

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.00093

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.00067

LIST_S2

Benign

0.21

T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.030

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

N;.

PhyloP100

0.20

PrimateAI

Benign

0.26

PROVEAN

Benign

1.1

N;N

REVEL

Benign

0.074

Sift

Benign

0.80

T;T

Sift4G

Benign

0.36

T;.

Polyphen

0.0

B;.

Vest4

0.038

MutPred

0.34

Loss of MoRF binding (P = 0.0672);.;

MVP

0.088

MPC

0.19

ClinPred

0.035

GERP RS

-0.064

Varity_R

0.070

gMVP

0.48

Mutation Taster

=100/0

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over