9-74842330-G-C

Variant names:

• chr9-74842330-G-C
• rs121912624
• NM_017662.5:c.166C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R56Q) has been classified as Uncertain significance.

• 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
• Publications: 8 publications found

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]

TRPM6 Gene-Disease associations (from GenCC):

• intestinal hypomagnesemia 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017662.5. 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
	TRPM6	NM_017662.5	MANE Select	c.166C>G	p.Arg56Gly	missense	Exon 4 of 39	NP_060132.3
	TRPM6	NM_001177310.2		c.151C>G	p.Arg51Gly	missense	Exon 4 of 39	NP_001170781.1	Q9BX84-2
	TRPM6	NM_001177311.2		c.151C>G	p.Arg51Gly	missense	Exon 4 of 39	NP_001170782.1	Q9BX84-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM6	ENST00000360774.6	TSL:1 MANE Select	c.166C>G	p.Arg56Gly	missense	Exon 4 of 39	ENSP00000354006.1	Q9BX84-1
	TRPM6	ENST00000361255.7	TSL:1	c.151C>G	p.Arg51Gly	missense	Exon 4 of 39	ENSP00000354962.3	Q9BX84-3
	TRPM6	ENST00000449912.6	TSL:1	c.151C>G	p.Arg51Gly	missense	Exon 4 of 39	ENSP00000396672.2	Q9BX84-2

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

African (AFR) AF: 0.0000242 AC: 1 AN: 41332

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.087
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.2
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.97	D
Vest4		0.54
MutPred		0.64		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
Mutation Taster		=57/43	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: rs121912624; hg19: chr9-77457246; COSMIC: COSV62518604;