Genetic Variant TRPM6:p.Thr2Arg (chr9-74887244-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000361255.7(TRPM6):c.5C>G(p.Thr2Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. 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. T2I) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TRPM6
ENST00000361255.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0270

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

intestinal hypomagnesemia 1
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

TRPM6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10963535).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361255.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRPM6	NM_017662.5	MANE Select	c.33+580C>G		intron	N/A	NP_060132.3
TRPM6	NM_001177311.2		c.5C>G	p.Thr2Arg	missense	Exon 1 of 39	NP_001170782.1
TRPM6	NM_001177310.2		c.18+387C>G		intron	N/A	NP_001170781.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRPM6	ENST00000361255.7	TSL:1	c.5C>G	p.Thr2Arg	missense	Exon 1 of 39	ENSP00000354962.3
TRPM6	ENST00000360774.6	TSL:1 MANE Select	c.33+580C>G		intron	N/A	ENSP00000354006.1
TRPM6	ENST00000449912.6	TSL:1	c.18+387C>G		intron	N/A	ENSP00000396672.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1118698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

530356

African (AFR)

AF:

0.00

AC:

AN:

24052

American (AMR)

AF:

0.00

AC:

AN:

11750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14940

East Asian (EAS)

AF:

0.00

AC:

AN:

28758

South Asian (SAS)

AF:

0.00

AC:

AN:

26112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4654

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

940028

Other (OTH)

AF:

0.00

AC:

AN:

45588

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

41168

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.97

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.35

M_CAP

Benign

0.067

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

PhyloP100

0.027

PrimateAI

Benign

0.48

PROVEAN

Benign

0.24

REVEL

Benign

0.055

Sift

Uncertain

0.015

Sift4G

Benign

0.13

Polyphen

0.0

Vest4

0.067

MutPred

0.28

Gain of MoRF binding (P = 2e-04)

MVP

0.043

ClinPred

0.12

GERP RS

1.9

PromoterAI

-0.063

Neutral

(source)

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over