7-142871843-A-T

Variant names:

• chr7-142871843-A-T
• rs4987682
• NM_018646.6:c.2162T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018646.6(TRPV6):​c.2162T>A​(p.Met721Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign 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. M721T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRPV6 NM_018646.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069013864).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV6	NM_018646.6	MANE Select	c.2162T>A	p.Met721Lys	missense	Exon 15 of 15	NP_061116.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV6	ENST00000359396.9	TSL:1 MANE Select	c.2162T>A	p.Met721Lys	missense	Exon 15 of 15	ENSP00000352358.5
	TRPV6	ENST00000485138.5	TSL:2	n.1772T>A		non_coding_transcript_exon	Exon 9 of 9
	TRPV6	ENST00000615386.4	TSL:2	n.9803T>A		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.3
DANN	Benign	0.78
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.061	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.1
PrimateAI	Benign	0.34	T
REVEL	Benign	0.029
Sift4G	Benign	0.57	T
Vest4		0.12
MVP		0.081
MPC		0.44
ClinPred		0.14	T
GERP RS		1.3
Varity_R		0.20
gMVP		0.37
Mutation Taster		=100/0	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: rs4987682; hg19: chr7-142569596;