9-74842330-G-C

Position:

• chr9-74842330-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017662.5(TRPM6):​c.166C>G​(p.Arg56Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 151,870 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: TRPM6 NM_017662.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.20

Genes affected

TRPM6 (HGNC:17995): (transient receptor potential cation channel subfamily M member 6) This gene is predominantly expressed in the kidney and colon, and encodes a protein containing an ion channel domain and a protein kinase domain. It is crucial for magnesium homeostasis, and plays an essential role in epithelial magnesium transport and in the active magnesium absorption in the gut and kidney. Mutations in this gene are associated with hypomagnesemia with secondary hypocalcemia. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM6	NM_017662.5	c.166C>G	p.Arg56Gly	missense_variant	4/39	ENST00000360774.6	NP_060132.3
TRPM6	NM_001177310.2	c.151C>G	p.Arg51Gly	missense_variant	4/39		NP_001170781.1
TRPM6	NM_001177311.2	c.151C>G	p.Arg51Gly	missense_variant	4/39		NP_001170782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM6	ENST00000360774.6	c.166C>G	p.Arg56Gly	missense_variant	4/39	1	NM_017662.5	ENSP00000354006	P4
TRPM6	ENST00000361255.7	c.151C>G	p.Arg51Gly	missense_variant	4/39	1		ENSP00000354962	A2
TRPM6	ENST00000449912.6	c.151C>G	p.Arg51Gly	missense_variant	4/39	1		ENSP00000396672	A2
TRPM6	ENST00000359047.2	c.166C>G	p.Arg56Gly	missense_variant	4/8	5		ENSP00000351942

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151870 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151870 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74160

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	.;.;D;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.087
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.4	.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.6	D;D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.97	D;.;D;D
Vest4		0.54
MutPred		0.64		.;.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.67
MPC		0.73
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.48
gMVP		0.74

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: rs121912624; hg19: chr9-77457246; COSMIC: COSV62518604;