rs121912624

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr9-74842330-G-A
• chr9-74842330-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017662.5(TRPM6):​c.166C>T​(p.Arg56*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000164 in 1,461,880 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TRPM6 NM_017662.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-74842330-G-A is Pathogenic according to our data. Variant chr9-74842330-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM6	NM_017662.5	c.166C>T	p.Arg56*	stop_gained	Exon 4 of 39	ENST00000360774.6	NP_060132.3
TRPM6	NM_001177310.2	c.151C>T	p.Arg51*	stop_gained	Exon 4 of 39		NP_001170781.1
TRPM6	NM_001177311.2	c.151C>T	p.Arg51*	stop_gained	Exon 4 of 39		NP_001170782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM6	ENST00000360774.6	c.166C>T	p.Arg56*	stop_gained	Exon 4 of 39	1	NM_017662.5	ENSP00000354006.1
TRPM6	ENST00000361255.7	c.151C>T	p.Arg51*	stop_gained	Exon 4 of 39	1		ENSP00000354962.3
TRPM6	ENST00000449912.6	c.151C>T	p.Arg51*	stop_gained	Exon 4 of 39	1		ENSP00000396672.2
TRPM6	ENST00000359047.2	c.166C>T	p.Arg56*	stop_gained	Exon 4 of 8	5		ENSP00000351942.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251484 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461880 Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intestinal hypomagnesemia 1 Pathogenic:2

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed stop gained c.166C>T(p.Arg56Ter) variant in TRPM6 gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with Primary hypomagnesemia with secondary hypocalcemia (HSH) (Astor et al., 2015). This variant is reported with the allele frequency of 0.0008% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRPM6 are known to be pathogenic (Schlingmann et al., 2005). Computational evidence (MutationTaster - Disease causing automatic) predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Likely Pathogenic. -

Jun 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

May 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3582). This premature translational stop signal has been observed in individual(s) with primary hypomagnesemia and secondary hypocalcemia (PMID: 12032570). This variant is present in population databases (rs121912624, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg56*) in the TRPM6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRPM6 are known to be pathogenic (PMID: 16107578). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.82
GERP RS		3.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: COSV62502510;