rs2151424

Variant names:

• chr9-74791365-C-T
• rs2151424
• NM_017662.5:c.2538+1259G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017662.5(TRPM6):​c.2538+1259G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 152,010 control chromosomes in the GnomAD database, including 6,146 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (6146 hom., cov: 32)
• Consequence: TRPM6 NM_017662.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.677
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM6	NM_017662.5	c.2538+1259G>A		intron_variant	Intron 19 of 38	ENST00000360774.6	NP_060132.3
TRPM6	NM_001177310.2	c.2523+1259G>A		intron_variant	Intron 19 of 38		NP_001170781.1
TRPM6	NM_001177311.2	c.2523+1259G>A		intron_variant	Intron 19 of 38		NP_001170782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM6	ENST00000360774.6	c.2538+1259G>A		intron_variant	Intron 19 of 38	1	NM_017662.5	ENSP00000354006.1
TRPM6	ENST00000361255.7	c.2523+1259G>A		intron_variant	Intron 19 of 38	1		ENSP00000354962.3
TRPM6	ENST00000449912.6	c.2523+1259G>A		intron_variant	Intron 19 of 38	1		ENSP00000396672.2
TRPM6	ENST00000715553.1	n.2538+1259G>A		intron_variant	Intron 19 of 39			ENSP00000520473.1

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42419 AN: 151892 Hom.: 6132 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.258

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.279 AC: 42481 AN: 152010 Hom.: 6146 Cov.: 32 AF XY: 0.275 AC XY: 20438 AN XY: 74292

African (AFR) AF: 0.346 AC: 14341 AN: 41440

American (AMR) AF: 0.206 AC: 3137 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1001 AN: 3466

East Asian (EAS) AF: 0.118 AC: 608 AN: 5172

South Asian (SAS) AF: 0.282 AC: 1356 AN: 4816

European-Finnish (FIN) AF: 0.265 AC: 2801 AN: 10558

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18345 AN: 67978

Other (OTH) AF: 0.263 AC: 557 AN: 2114

Alfa AF: 0.268 Hom.: 14993

Bravo AF: 0.274

Asia WGS AF: 0.224 AC: 779 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.57
DANN	Benign	0.28
PhyloP100		-0.68
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: rs2151424; hg19: chr9-77406281; COSMIC: COSV62505663;