9-74761731-T-C

Position:

chr9-74761731-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017662.5(TRPM6):c.4750A>G(p.Lys1584Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,611,138 control chromosomes in the GnomAD database, including 31,413 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 5010 hom., cov: 32)

Exomes 𝑓: 0.18 ( 26403 hom. )

Consequence

TRPM6
NM_017662.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.82

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004234761).

BP6

Variant 9-74761731-T-C is Benign according to our data. Variant chr9-74761731-T-C is described in ClinVar as [Benign]. Clinvar id is 367301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-74761731-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM6	NM_017662.5 linkuse as main transcript	c.4750A>G	p.Lys1584Glu	missense_variant	27/39	ENST00000360774.6	NP_060132.3	Q9BX84-1
TRPM6	NM_001177310.2 linkuse as main transcript	c.4735A>G	p.Lys1579Glu	missense_variant	27/39		NP_001170781.1	Q9BX84-2
TRPM6	NM_001177311.2 linkuse as main transcript	c.4735A>G	p.Lys1579Glu	missense_variant	27/39		NP_001170782.1	Q9BX84-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TRPM6	ENST00000360774.6 linkuse as main transcript	c.4750A>G	p.Lys1584Glu	missense_variant	27/39	1	NM_017662.5	ENSP00000354006.1	Q9BX84-1
TRPM6	ENST00000361255.7 linkuse as main transcript	c.4735A>G	p.Lys1579Glu	missense_variant	27/39	1		ENSP00000354962.3	Q9BX84-3
TRPM6	ENST00000449912.6 linkuse as main transcript	c.4735A>G	p.Lys1579Glu	missense_variant	27/39	1		ENSP00000396672.2	Q9BX84-2

Frequencies

GnomAD3 genomes

AF:

0.232

AC:

35239

AN:

152024

Hom.:

5005

Cov.:

show subpopulations

Gnomad AFR

AF:

0.391

Gnomad AMI

AF:

0.174

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.164

Gnomad EAS

AF:

0.331

Gnomad SAS

AF:

0.338

Gnomad FIN

AF:

0.128

Gnomad MID

AF:

0.207

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.214

GnomAD3 exomes

AF:

0.201

AC:

50449

AN:

251360

Hom.:

6221

AF XY:

0.206

AC XY:

27976

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.400

Gnomad AMR exome

AF:

0.107

Gnomad ASJ exome

AF:

0.165

Gnomad EAS exome

AF:

0.319

Gnomad SAS exome

AF:

0.345

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.161

Gnomad OTH exome

AF:

0.180

GnomAD4 exome

AF:

0.177

AC:

258690

AN:

1458996

Hom.:

26403

Cov.:

AF XY:

0.182

AC XY:

132202

AN XY:

726008

show subpopulations

Gnomad4 AFR exome

AF:

0.400

Gnomad4 AMR exome

AF:

0.113

Gnomad4 ASJ exome

AF:

0.165

Gnomad4 EAS exome

AF:

0.335

Gnomad4 SAS exome

AF:

0.342

Gnomad4 FIN exome

AF:

0.130

Gnomad4 NFE exome

AF:

0.156

Gnomad4 OTH exome

AF:

0.196

GnomAD4 genome

AF:

0.232

AC:

35288

AN:

152142

Hom.:

5010

Cov.:

AF XY:

0.230

AC XY:

17077

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.391

Gnomad4 AMR

AF:

0.158

Gnomad4 ASJ

AF:

0.164

Gnomad4 EAS

AF:

0.331

Gnomad4 SAS

AF:

0.338

Gnomad4 FIN

AF:

0.128

Gnomad4 NFE

AF:

0.157

Gnomad4 OTH

AF:

0.219

Alfa

AF:

0.177

Hom.:

6850

Bravo

AF:

0.240

TwinsUK

AF:

0.152

AC:

563

ALSPAC

AF:

0.158

AC:

608

ESP6500AA

AF:

0.392

AC:

1727

ESP6500EA

AF:

0.155

AC:

1335

ExAC

AF:

0.211

AC:

25633

Asia WGS

AF:

0.350

AC:

1217

AN:

3478

EpiCase

AF:

0.169

EpiControl

AF:

0.167

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Intestinal hypomagnesemia 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;.;T

Eigen

Benign

0.053

Eigen_PC

Benign

0.040

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.81

T;T;T

MetaRNN

Benign

0.0042

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

.;.;L

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.083

Sift

Uncertain

0.0020

D;D;D

Sift4G

Benign

0.24

T;T;T

Polyphen

0.68

P;P;P

Vest4

0.24

MPC

0.51

ClinPred

0.024

GERP RS

4.6

Varity_R

0.22

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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