7-142871727-T-A

Variant names:

• chr7-142871727-T-A
• rs1794934658
• NM_018646.6:c.2278A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018646.6(TRPV6):​c.2278A>T​(p.Ser760Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,451,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TRPV6 NM_018646.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00500
• Publications: 0 publications found

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]

TRPV6 Gene-Disease associations (from GenCC):

• hyperparathyroidism, transient neonatal

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P
• intestinal hypomagnesemia 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• pancreatitis

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• neonatal severe primary hyperparathyroidism

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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=0.053666294).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018646.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV6	NM_018646.6	MANE Select	c.2278A>T	p.Ser760Cys	missense	Exon 15 of 15	NP_061116.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV6	ENST00000359396.9	TSL:1 MANE Select	c.2278A>T	p.Ser760Cys	missense	Exon 15 of 15	ENSP00000352358.5	Q9H1D0-1
	TRPV6	ENST00000485138.5	TSL:2	n.1888A>T		non_coding_transcript_exon	Exon 9 of 9
	TRPV6	ENST00000615386.4	TSL:2	n.9919A>T		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1451946 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720884

African (AFR) AF: 0.00 AC: 0 AN: 33174

American (AMR) AF: 0.00 AC: 0 AN: 43916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25660

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.00 AC: 0 AN: 85416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1105444

Other (OTH) AF: 0.00 AC: 0 AN: 59898

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.0050
PrimateAI	Benign	0.28	T
REVEL	Benign	0.045
Sift4G	Uncertain	0.019	D
Vest4		0.086
MVP		0.20
MPC		0.27
ClinPred		0.14	T
GERP RS		1.4
Varity_R		0.055
gMVP		0.12
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs1794934658; hg19: chr7-142569480;