rs4987683

Variant names:

• chr7-142871803-A-G
• rs4987683
• NM_018646.6:c.2202T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_018646.6(TRPV6):​c.2202T>C​(p.Asn734Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 1,614,038 control chromosomes in the GnomAD database, including 718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.039 (154 hom., cov: 33)
  • Exomes 𝑓: 0.025 (564 hom.)
• Consequence: TRPV6 NM_018646.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.06
• Publications: 4 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 7-142871803-A-G is Benign according to our data. Variant chr7-142871803-A-G is described in ClinVar as Benign. ClinVar VariationId is 2800936.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

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.2202T>C	p.Asn734Asn	synonymous	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.2202T>C	p.Asn734Asn	synonymous	Exon 15 of 15	ENSP00000352358.5	Q9H1D0-1
	TRPV6	ENST00000485138.5	TSL:2	n.1812T>C		non_coding_transcript_exon	Exon 9 of 9
	TRPV6	ENST00000615386.4	TSL:2	n.9843T>C		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 5899 AN: 152056 Hom.: 152 Cov.: 33

Gnomad AFR AF: 0.0836

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00472

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0258

Gnomad OTH AF: 0.0435

GnomAD2 exomes AF: 0.0226 AC: 5679 AN: 251444 AF XY: 0.0205

Gnomad AFR exome AF: 0.0823

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.0220

Gnomad EAS exome AF: 0.000652

Gnomad FIN exome AF: 0.00642

Gnomad NFE exome AF: 0.0275

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0252 AC: 36907 AN: 1461864 Hom.: 564 Cov.: 31 AF XY: 0.0244 AC XY: 17710 AN XY: 727238

African (AFR) AF: 0.0846 AC: 2831 AN: 33478

American (AMR) AF: 0.0188 AC: 840 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 553 AN: 26134

East Asian (EAS) AF: 0.00247 AC: 98 AN: 39700

South Asian (SAS) AF: 0.00329 AC: 284 AN: 86256

European-Finnish (FIN) AF: 0.00693 AC: 370 AN: 53420

Middle Eastern (MID) AF: 0.0366 AC: 211 AN: 5768

European-Non Finnish (NFE) AF: 0.0270 AC: 30061 AN: 1111998

Other (OTH) AF: 0.0275 AC: 1659 AN: 60394

GnomAD4 genome AF: 0.0388 AC: 5903 AN: 152174 Hom.: 154 Cov.: 33 AF XY: 0.0359 AC XY: 2669 AN XY: 74422

African (AFR) AF: 0.0835 AC: 3466 AN: 41502

American (AMR) AF: 0.0258 AC: 394 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 81 AN: 3462

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.00472 AC: 50 AN: 10602

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0258 AC: 1757 AN: 67992

Other (OTH) AF: 0.0425 AC: 90 AN: 2116

Alfa AF: 0.0329 Hom.: 54

Bravo AF: 0.0429

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.0302

EpiControl AF: 0.0299

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	TRPV6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.5
DANN	Benign	0.56
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4987683; hg19: chr7-142569556; COSMIC: COSV108183018; COSMIC: COSV108183018;