NM_019841.7:c.1277A>G

Variant names:

• chr7-142915316-T-C
• NM_019841.7:c.1277A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_019841.7(TRPV5):​c.1277A>G​(p.His426Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TRPV5 NM_019841.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.63
• Publications: 0 publications found

Genes affected

TRPV5 (HGNC:3145): (transient receptor potential cation channel subfamily V member 5) This gene is a member of the transient receptor family and the TrpV subfamily. The calcium-selective channel encoded by this gene has 6 transmembrane-spanning domains, multiple potential phosphorylation sites, an N-linked glycosylation site, and 5 ANK repeats. This protein forms homotetramers or heterotetramers and is activated by a low internal calcium level. [provided by RefSeq, Jul 2008]

TRPV5 Gene-Disease associations (from GenCC):

• hypercalciuria, absorptive, 2

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019841.7. 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
	TRPV5	NM_019841.7	MANE Select	c.1277A>G	p.His426Arg	missense	Exon 10 of 15	NP_062815.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV5	ENST00000265310.6	TSL:1 MANE Select	c.1277A>G	p.His426Arg	missense	Exon 10 of 15	ENSP00000265310.1	Q9NQA5-1
	TRPV5	ENST00000439304.5	TSL:5	c.1112A>G	p.His371Arg	missense	Exon 9 of 14	ENSP00000406361.1	H7C2J6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457192 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725122

African (AFR) AF: 0.00 AC: 0 AN: 33024

American (AMR) AF: 0.00 AC: 0 AN: 42830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25910

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 85636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110858

Other (OTH) AF: 0.00 AC: 0 AN: 60154

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		4.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0060	D
Vest4		0.93
MutPred		0.74		Gain of sheet (P = 0.0266)
MVP		1.0
MPC		0.73
ClinPred		0.99	D
GERP RS		5.3
gMVP		0.42
Mutation Taster		=73/27	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

hg19: chr7-142612486;