rs759393722

Variant names:

• chr7-142874958-C-G
• rs759393722
• NM_018646.6:c.1352G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-142874958-C-G
• chr7-142874958-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_018646.6(TRPV6):​c.1352G>C​(p.Gly451Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G451E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TRPV6 NM_018646.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.02
• Publications: 2 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-142874958-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 590768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV6	NM_018646.6	c.1352G>C	p.Gly451Ala	missense_variant	Exon 10 of 15	ENST00000359396.9	NP_061116.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV6	ENST00000359396.9	c.1352G>C	p.Gly451Ala	missense_variant	Exon 10 of 15	1	NM_018646.6	ENSP00000352358.5
TRPV6	ENST00000436401.1	c.101G>C	p.Gly34Ala	missense_variant	Exon 4 of 6	4		ENSP00000411100.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.4	.;.;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0060	.;.;D
Sift4G	Uncertain	0.022	D;.;D
Vest4		0.92
MVP		0.76
MPC		1.0
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.52
gMVP		0.81
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs759393722; hg19: chr7-142572711;