rs3750425

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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

Publications

43 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: Orphanet, Labcorp Genetics (formerly Invitae)

TRPM6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 367306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017662.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPM6	NM_017662.5	MANE Select	c.4177G>A	p.Val1393Ile	missense	Exon 26 of 39	NP_060132.3
TRPM6	NM_001177310.2		c.4162G>A	p.Val1388Ile	missense	Exon 26 of 39	NP_001170781.1	Q9BX84-2
TRPM6	NM_001177311.2		c.4162G>A	p.Val1388Ile	missense	Exon 26 of 39	NP_001170782.1	Q9BX84-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPM6	ENST00000360774.6	TSL:1 MANE Select	c.4177G>A	p.Val1393Ile	missense	Exon 26 of 39	ENSP00000354006.1	Q9BX84-1
TRPM6	ENST00000361255.7	TSL:1	c.4162G>A	p.Val1388Ile	missense	Exon 26 of 39	ENSP00000354962.3	Q9BX84-3
TRPM6	ENST00000449912.6	TSL:1	c.4162G>A	p.Val1388Ile	missense	Exon 26 of 39	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

GnomAD2 exomes

AF:

0.119

AC:

29759

AN:

251038

AF XY:

0.122

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 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

African (AFR)

AF:

0.272

AC:

9123

AN:

33480

American (AMR)

AF:

0.0758

AC:

3391

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0789

AC:

2063

AN:

26136

East Asian (EAS)

AF:

0.156

AC:

6213

AN:

39700

South Asian (SAS)

AF:

0.226

AC:

19529

AN:

86258

European-Finnish (FIN)

AF:

0.0670

AC:

3576

AN:

53410

Middle Eastern (MID)

AF:

0.144

AC:

831

AN:

5768

European-Non Finnish (NFE)

AF:

0.0873

AC:

97060

AN:

1112000

Other (OTH)

AF:

0.110

AC:

6667

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

9164

18329

27493

36658

45822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3830

7660

11490

15320

19150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.141

AC:

21498

AN:

152160

Hom.:

2094

Cov.:

AF XY:

0.140

AC XY:

10403

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.261

AC:

10816

AN:

41486

American (AMR)

AF:

0.0960

AC:

1466

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0795

AC:

276

AN:

3472

East Asian (EAS)

AF:

0.157

AC:

809

AN:

5168

South Asian (SAS)

AF:

0.223

AC:

1075

AN:

4826

European-Finnish (FIN)

AF:

0.0615

AC:

652

AN:

10596

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0887

AC:

6032

AN:

68016

Other (OTH)

AF:

0.128

AC:

270

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

881

1762

2643

3524

4405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.107

Hom.:

4700

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Intestinal hypomagnesemia 1 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.010

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.12

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.093

MetaRNN

Benign

0.0043

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

-0.43

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.030

REVEL

Benign

0.043

Sift

Benign

0.17

Sift4G

Benign

0.23

Polyphen

0.30

Vest4

0.022

MPC

0.20

ClinPred

0.0018

GERP RS

0.44

Varity_R

0.023

gMVP

0.11

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over