9-74762494-C-T

Variant names:

• chr9-74762494-C-T
• rs3750425
• NM_017662.5:c.4177G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.426
• Publications: 43 publications found

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

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM6	NM_017662.5	c.4177G>A	p.Val1393Ile	missense_variant	Exon 26 of 39	ENST00000360774.6	NP_060132.3
TRPM6	NM_001177310.2	c.4162G>A	p.Val1388Ile	missense_variant	Exon 26 of 39		NP_001170781.1
TRPM6	NM_001177311.2	c.4162G>A	p.Val1388Ile	missense_variant	Exon 26 of 39		NP_001170782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM6	ENST00000360774.6	c.4177G>A	p.Val1393Ile	missense_variant	Exon 26 of 39	1	NM_017662.5	ENSP00000354006.1
TRPM6	ENST00000361255.7	c.4162G>A	p.Val1388Ile	missense_variant	Exon 26 of 39	1		ENSP00000354962.3
TRPM6	ENST00000449912.6	c.4162G>A	p.Val1388Ile	missense_variant	Exon 26 of 39	1		ENSP00000396672.2
TRPM6	ENST00000715553.1	n.4177G>A		non_coding_transcript_exon_variant	Exon 26 of 40			ENSP00000520473.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21454 AN: 152042 Hom.: 2087 Cov.: 32

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

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.: 34 AF XY: 0.105 AC XY: 76591 AN XY: 727238

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

GnomAD4 genome AF: 0.141 AC: 21498 AN: 152160 Hom.: 2094 Cov.: 32 AF XY: 0.140 AC XY: 10403 AN XY: 74392

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: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0887 AC: 6032 AN: 68016

Other (OTH) AF: 0.128 AC: 270 AN: 2112

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intestinal hypomagnesemia 1 Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
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	N
LIST_S2	Benign	0.093	T;T;T
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;.;L
PhyloP100		-0.43
PrimateAI	Benign	0.21	T
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	T
GERP RS		0.44
Varity_R		0.023
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3750425; hg19: chr9-77377410; COSMIC: COSV62513372;