7-142871948-C-T

Variant names:

• chr7-142871948-C-T
• rs200072889
• NM_018646.6:c.2057G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018646.6(TRPV6):​c.2057G>A​(p.Arg686His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,457,706 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TRPV6 NM_018646.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV6	NM_018646.6	c.2057G>A	p.Arg686His	missense_variant	Exon 15 of 15	ENST00000359396.9	NP_061116.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV6	ENST00000359396.9	c.2057G>A	p.Arg686His	missense_variant	Exon 15 of 15	1	NM_018646.6	ENSP00000352358.5
TRPV6	ENST00000485138.5	n.1667G>A		non_coding_transcript_exon_variant	Exon 9 of 9	2
TRPV6	ENST00000615386.4	n.9698G>A		non_coding_transcript_exon_variant	Exon 12 of 12	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1457706 Hom.: 0 Cov.: 31 AF XY: 0.0000166 AC XY: 12 AN XY: 724716

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1937G>A (p.R646H) alteration is located in exon 15 (coding exon 15) of the TRPV6 gene. This alteration results from a G to A substitution at nucleotide position 1937, causing the arginine (R) at amino acid position 646 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.00030	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.59	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.12
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.0090	D;.
Vest4		0.10
MVP		0.80
MPC		0.36
ClinPred		0.92	D
GERP RS		5.5
Varity_R		0.46
gMVP		0.66

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

Other links and lift over

dbSNP: rs200072889; hg19: chr7-142569701;