9-74762494-C-T

Position:

chr9-74762494-C-T

Variant summary

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

The NM_017662.5(TRPM6):c.4177G>A(p.Val1393Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,614,024 control chromosomes in the GnomAD database, including 11,058 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 2094 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8964 hom. )

Consequence

TRPM6
NM_017662.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.426

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=0.004346907).

BP6

Variant 9-74762494-C-T is Benign according to our data. Variant chr9-74762494-C-T is described in ClinVar as [Benign]. Clinvar id is 367306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-74762494-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM6	NM_017662.5 link	c.4177G>A	p.Val1393Ile	missense_variant	26/39	ENST00000360774.6	NP_060132.3	Q9BX84-1
TRPM6	NM_001177310.2 link	c.4162G>A	p.Val1388Ile	missense_variant	26/39		NP_001170781.1	Q9BX84-2
TRPM6	NM_001177311.2 link	c.4162G>A	p.Val1388Ile	missense_variant	26/39		NP_001170782.1	Q9BX84-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TRPM6	ENST00000360774.6 link	c.4177G>A	p.Val1393Ile	missense_variant	26/39	1	NM_017662.5	ENSP00000354006.1	Q9BX84-1
TRPM6	ENST00000361255.7 link	c.4162G>A	p.Val1388Ile	missense_variant	26/39	1		ENSP00000354962.3	Q9BX84-3
TRPM6	ENST00000449912.6 link	c.4162G>A	p.Val1388Ile	missense_variant	26/39	1		ENSP00000396672.2	Q9BX84-2

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21454

AN:

152042

Hom.:

2087

Cov.:

show subpopulations

Gnomad AFR

AF:

0.261

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.0958

Gnomad ASJ

AF:

0.0795

Gnomad EAS

AF:

0.156

Gnomad SAS

AF:

0.222

Gnomad FIN

AF:

0.0615

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.0887

Gnomad OTH

AF:

0.126

GnomAD3 exomes

AF:

0.119

AC:

29759

AN:

251038

Hom.:

2289

AF XY:

0.122

AC XY:

16577

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.271

Gnomad AMR exome

AF:

0.0720

Gnomad ASJ exome

AF:

0.0809

Gnomad EAS exome

AF:

0.161

Gnomad SAS exome

AF:

0.227

Gnomad FIN exome

AF:

0.0652

Gnomad NFE exome

AF:

0.0891

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.102

AC:

148453

AN:

1461864

Hom.:

8964

Cov.:

AF XY:

0.105

AC XY:

76591

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.272

Gnomad4 AMR exome

AF:

0.0758

Gnomad4 ASJ exome

AF:

0.0789

Gnomad4 EAS exome

AF:

0.156

Gnomad4 SAS exome

AF:

0.226

Gnomad4 FIN exome

AF:

0.0670

Gnomad4 NFE exome

AF:

0.0873

Gnomad4 OTH exome

AF:

0.110

GnomAD4 genome

AF:

0.141

AC:

21498

AN:

152160

Hom.:

2094

Cov.:

AF XY:

0.140

AC XY:

10403

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.261

Gnomad4 AMR

AF:

0.0960

Gnomad4 ASJ

AF:

0.0795

Gnomad4 EAS

AF:

0.157

Gnomad4 SAS

AF:

0.223

Gnomad4 FIN

AF:

0.0615

Gnomad4 NFE

AF:

0.0887

Gnomad4 OTH

AF:

0.128

Alfa

AF:

0.102

Hom.:

2245

Bravo

AF:

0.148

TwinsUK

AF:

0.0804

AC:

298

ALSPAC

AF:

0.0895

AC:

345

ESP6500AA

AF:

0.258

AC:

1138

ESP6500EA

AF:

0.0851

AC:

732

ExAC

AF:

0.124

AC:

15102

Asia WGS

AF:

0.181

AC:

631

AN:

3478

EpiCase

AF:

0.0942

EpiControl

AF:

0.0937

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	- -

Intestinal hypomagnesemia 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.010

DANN

Benign

0.57

DEOGEN2

Benign

0.12

.;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.093

T;T;T

MetaRNN

Benign

0.0043

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;.;L

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.030

N;N;N

REVEL

Benign

0.043

Sift

Benign

0.17

T;T;T

Sift4G

Benign

0.23

T;T;T

Polyphen

0.30

B;B;B

Vest4

0.022

MPC

0.20

ClinPred

0.0018

GERP RS

0.44

Varity_R

0.023

gMVP

0.11

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