7-142872409-C-G

Position:

• chr7-142872409-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The ENST00000359396.9(TRPV6):​c.1978G>C​(p.Gly660Arg) 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRPV6 ENST00000359396.9 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.88

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878
• PP5: Variant 7-142872409-C-G is Pathogenic according to our data. Variant chr7-142872409-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 818220.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPV6	NM_018646.6	c.1978G>C	p.Gly660Arg	missense_variant	14/15	ENST00000359396.9	NP_061116.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPV6	ENST00000359396.9	c.1978G>C	p.Gly660Arg	missense_variant	14/15	1	NM_018646.6	ENSP00000352358	P5
TRPV6	ENST00000485138.5	n.1588G>C		non_coding_transcript_exon_variant	8/9	2
TRPV6	ENST00000615386.4	n.9619G>C		non_coding_transcript_exon_variant	11/12	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperparathyroidism;C1833144:Slender long bone;na:Embryonic calcium dysregulation;na:Metaphyseal fractures Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Exeter Molecular Genetics Laboratory

Jul 20, 2018

The p.(Gly660Arg) variant has been reported in the gnomAD database at a low frequency (5/138,451 individuals [1/27,690]). No homozygotes were reported. (PM2_Moderate). The p.(Gly660Arg) variant was detected in trans with a pathogenic nonsense variant, p.(Arg510Ter) (PM3_Moderate). The p.Gly660 residue is conserved across 19 species (to lamprey) and has a consurf score of 9. The p.(Gly660Arg) variant is predicted by SIFT, PolyPhen and AlignGVGD to have a deleterious effect on protein function (PP3_Supporting). The TRPV6 variants were identified by a gene-agnostic inheritance based strategy. This patient presented with embryonic calcium dysregulation, with gracile long bones and ribs. Calcium homeostasis returned post-natally, indicating an embryonically active calcium channel. TRPV6 encodes a calcium channel which shows exclusive expression in the human placenta (PP4_Supporting). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.29	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
REVEL	Pathogenic	0.67
Sift4G	Pathogenic	0.0	D;.
Vest4		0.89
MVP		0.70
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.89
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs780306040; hg19: chr7-142570162;