rs2274924

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.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. 15/21 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

Publications

62 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=0.004234761).

BP6

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

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.386 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.4750A>G	p.Lys1584Glu	missense	Exon 27 of 39	NP_060132.3
TRPM6	NM_001177310.2		c.4735A>G	p.Lys1579Glu	missense	Exon 27 of 39	NP_001170781.1	Q9BX84-2
TRPM6	NM_001177311.2		c.4735A>G	p.Lys1579Glu	missense	Exon 27 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.4750A>G	p.Lys1584Glu	missense	Exon 27 of 39	ENSP00000354006.1	Q9BX84-1
TRPM6	ENST00000361255.7	TSL:1	c.4735A>G	p.Lys1579Glu	missense	Exon 27 of 39	ENSP00000354962.3	Q9BX84-3
TRPM6	ENST00000449912.6	TSL:1	c.4735A>G	p.Lys1579Glu	missense	Exon 27 of 39	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

GnomAD2 exomes

AF:

0.201

AC:

50449

AN:

251360

AF XY:

0.206

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 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

African (AFR)

AF:

0.400

AC:

13362

AN:

33376

American (AMR)

AF:

0.113

AC:

5047

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

4312

AN:

26116

East Asian (EAS)

AF:

0.335

AC:

13263

AN:

39648

South Asian (SAS)

AF:

0.342

AC:

29480

AN:

86182

European-Finnish (FIN)

AF:

0.130

AC:

6929

AN:

53402

Middle Eastern (MID)

AF:

0.225

AC:

1299

AN:

5764

European-Non Finnish (NFE)

AF:

0.156

AC:

173180

AN:

1109498

Other (OTH)

AF:

0.196

AC:

11818

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

10056

20113

30169

40226

50282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6488

12976

19464

25952

32440

<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:

0.232

AC:

35288

AN:

152142

Hom.:

5010

Cov.:

AF XY:

0.230

AC XY:

17077

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.391

AC:

16216

AN:

41468

American (AMR)

AF:

0.158

AC:

2415

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.164

AC:

570

AN:

3470

East Asian (EAS)

AF:

0.331

AC:

1715

AN:

5178

South Asian (SAS)

AF:

0.338

AC:

1631

AN:

4828

European-Finnish (FIN)

AF:

0.128

AC:

1351

AN:

10590

Middle Eastern (MID)

AF:

0.209

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.157

AC:

10708

AN:

68004

Other (OTH)

AF:

0.219

AC:

462

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1317

2635

3952

5270

6587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

372

744

1116

1488

1860

<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:

0.187

Hom.:

12216

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

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

0.10

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

0.053

Eigen_PC

Benign

0.040

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

PhyloP100

1.8

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.1

REVEL

Benign

0.083

Sift

Uncertain

0.0020

Sift4G

Benign

0.24

Polyphen

0.68

Vest4

0.24

MPC

0.51

ClinPred

0.024

GERP RS

4.6

Varity_R

0.22

gMVP

0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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