Variant rs121912625 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_017662.5(TRPM6):c.422C>T(p.Ser141Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,690 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TRPM6
NM_017662.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.85

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

PP5

Variant 9-74840146-G-A is Pathogenic according to our data. Variant chr9-74840146-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3585.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-74840146-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TRPM6	NM_017662.5 linkuse as main transcript	c.422C>T	p.Ser141Leu	missense_variant	5/39	ENST00000360774.6	NP_060132.3
TRPM6	NM_001177310.2 linkuse as main transcript	c.407C>T	p.Ser136Leu	missense_variant	5/39		NP_001170781.1
TRPM6	NM_001177311.2 linkuse as main transcript	c.407C>T	p.Ser136Leu	missense_variant	5/39		NP_001170782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM6	ENST00000360774.6 linkuse as main transcript	c.422C>T	p.Ser141Leu	missense_variant	5/39	1	NM_017662.5	ENSP00000354006	P4	Q9BX84-1
TRPM6	ENST00000361255.7 linkuse as main transcript	c.407C>T	p.Ser136Leu	missense_variant	5/39	1		ENSP00000354962	A2	Q9BX84-3
TRPM6	ENST00000449912.6 linkuse as main transcript	c.407C>T	p.Ser136Leu	missense_variant	5/39	1		ENSP00000396672	A2	Q9BX84-2
TRPM6	ENST00000359047.2 linkuse as main transcript	c.422C>T	p.Ser141Leu	missense_variant	5/8	5		ENSP00000351942

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251482

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461690

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Intestinal hypomagnesemia 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 02, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

.;.;D;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.94

D;D;D;D

MetaSVM

Benign

-0.92

MutationAssessor

Pathogenic

3.9

.;.;H;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.6

D;D;D;D

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.95

MutPred

0.82

.;.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.65

MPC

0.85

ClinPred

1.0

GERP RS

5.9

Varity_R

0.87

gMVP

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over