rs4987682

Positions:

• chr7-142871843-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018646.6(TRPV6):​c.2162T>C​(p.Met721Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0945 in 1,613,972 control chromosomes in the GnomAD database, including 15,697 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (6414 hom., cov: 33)
  • Exomes 𝑓: 0.083 (9283 hom.)
• Consequence: TRPV6 NM_018646.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.13

Genes affected

TRPV6 (HGNC:14006): (transient receptor potential cation channel subfamily V member 6) This gene encodes a member of a family of multipass membrane proteins that functions as calcium channels. The encoded protein contains N-terminal ankyrin repeats, which are required for channel assembly and regulation. Translation initiation for this protein occurs at a non-AUG start codon that is decoded as methionine. This gene is situated next to a closely related gene for transient receptor potential cation channel subfamily V member 5 (TRPV5). This locus has experienced positive selection in non-African populations, resulting in several non-synonymous codon differences among individuals of different genetic backgrounds. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.153571E-5).
• BP6: Variant 7-142871843-A-G is Benign according to our data. Variant chr7-142871843-A-G is described in ClinVar as [Benign]. Clinvar id is 2786649.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPV6	NM_018646.6	c.2162T>C	p.Met721Thr	missense_variant	15/15	ENST00000359396.9	NP_061116.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPV6	ENST00000359396.9	c.2162T>C	p.Met721Thr	missense_variant	15/15	1	NM_018646.6	ENSP00000352358	P5
TRPV6	ENST00000485138.5	n.1772T>C		non_coding_transcript_exon_variant	9/9	2
TRPV6	ENST00000615386.4	n.9803T>C		non_coding_transcript_exon_variant	12/12	2

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30573 AN: 151994 Hom.: 6395 Cov.: 33

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0648

Gnomad EAS AF: 0.0212

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0728

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0768

Gnomad OTH AF: 0.181

GnomAD3 exomes AF: 0.0919 AC: 23113 AN: 251440 Hom.: 2993 AF XY: 0.0800 AC XY: 10877 AN XY: 135894

Gnomad AFR exome AF: 0.548

Gnomad AMR exome AF: 0.0561

Gnomad ASJ exome AF: 0.0610

Gnomad EAS exome AF: 0.0202

Gnomad SAS exome AF: 0.0124

Gnomad FIN exome AF: 0.0779

Gnomad NFE exome AF: 0.0766

Gnomad OTH exome AF: 0.0830

GnomAD4 exome AF: 0.0834 AC: 121926 AN: 1461860 Hom.: 9283 Cov.: 31 AF XY: 0.0793 AC XY: 57702 AN XY: 727230

Gnomad4 AFR exome AF: 0.550

Gnomad4 AMR exome AF: 0.0598

Gnomad4 ASJ exome AF: 0.0603

Gnomad4 EAS exome AF: 0.0143

Gnomad4 SAS exome AF: 0.0123

Gnomad4 FIN exome AF: 0.0788

Gnomad4 NFE exome AF: 0.0782

Gnomad4 OTH exome AF: 0.0991

GnomAD4 genome AF: 0.201 AC: 30636 AN: 152112 Hom.: 6414 Cov.: 33 AF XY: 0.193 AC XY: 14364 AN XY: 74374

Gnomad4 AFR AF: 0.536

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.0648

Gnomad4 EAS AF: 0.0213

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.0728

Gnomad4 NFE AF: 0.0768

Gnomad4 OTH AF: 0.179

Alfa AF: 0.0990 Hom.: 2946

Bravo AF: 0.220

TwinsUK AF: 0.0820 AC: 304

ALSPAC AF: 0.0747 AC: 288

ESP6500AA AF: 0.530 AC: 2336

ESP6500EA AF: 0.0787 AC: 677

ExAC AF: 0.101 AC: 12225

Asia WGS AF: 0.0570 AC: 198 AN: 3478

EpiCase AF: 0.0748

EpiControl AF: 0.0788

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

TRPV6-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.60
DANN	Benign	0.66
DEOGEN2	Benign	0.16	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00046	N
LIST_S2	Benign	0.0069	T;T
MetaRNN	Benign	0.000072	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.32	T
REVEL	Benign	0.042
Sift4G	Benign	0.61	T;.
Vest4		0.012
MPC		0.32
ClinPred		0.00078	T
GERP RS		1.3
Varity_R		0.088
gMVP		0.21

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: rs4987682; hg19: chr7-142569596; COSMIC: COSV63891596; COSMIC: COSV63891596;