5-157087232-C-T

Position:

• chr5-157087232-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_032782.5(HAVCR2):​c.776G>A​(p.Arg259His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000872 in 1,613,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00090 (0 hom.)
• Consequence: HAVCR2 NM_032782.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.19

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009178638).
• BP6: Variant 5-157087232-C-T is Benign according to our data. Variant chr5-157087232-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1327999.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAVCR2	NM_032782.5	c.776G>A	p.Arg259His	missense_variant	7/7	ENST00000307851.9	NP_116171.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAVCR2	ENST00000307851.9	c.776G>A	p.Arg259His	missense_variant	7/7	1	NM_032782.5	ENSP00000312002.4

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000777 AC: 195 AN: 250862 Hom.: 0 AF XY: 0.000856 AC XY: 116 AN XY: 135580

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000657

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000899 AC: 1314 AN: 1461490 Hom.: 0 Cov.: 31 AF XY: 0.000967 AC XY: 703 AN XY: 727040

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000557

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74446

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000669

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000898 AC: 109

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 04, 2023	BP4 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	HAVCR2: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.7
DANN	Benign	0.79
DEOGEN2	Benign	0.0022	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.0092	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.41	N;N
REVEL	Benign	0.018
Sift	Benign	0.46	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.12	B;.
Vest4		0.046
MVP		0.088
MPC		0.17
ClinPred		0.013	T
GERP RS		-3.2
Varity_R		0.014
gMVP		0.28

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

Other links and lift over

dbSNP: rs138681649; hg19: chr5-156514243; COSMIC: COSV57153353;