rs875034

Variant names:

• chr9-74742127-A-G
• rs875034
• NM_017662.5:c.5200+434T>C

Variant summary

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

The NM_017662.5(TRPM6):​c.5200+434T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 152,014 control chromosomes in the GnomAD database, including 23,636 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 0.53 (23636 hom., cov: 32)
• Consequence: TRPM6 NM_017662.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.361
• Publications: 2 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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.79 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM6	NM_017662.5	MANE Select	c.5200+434T>C		intron	N/A	NP_060132.3
	TRPM6	NM_001177310.2		c.5185+434T>C		intron	N/A	NP_001170781.1
	TRPM6	NM_001177311.2		c.5185+434T>C		intron	N/A	NP_001170782.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM6	ENST00000360774.6	TSL:1 MANE Select	c.5200+434T>C		intron	N/A	ENSP00000354006.1
	TRPM6	ENST00000361255.7	TSL:1	c.5185+434T>C		intron	N/A	ENSP00000354962.3
	TRPM6	ENST00000449912.6	TSL:1	c.5185+434T>C		intron	N/A	ENSP00000396672.2

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79961 AN: 151896 Hom.: 23593 Cov.: 32

Gnomad AFR AF: 0.797

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.539

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

GnomAD4 genome AF: 0.527 AC: 80061 AN: 152014 Hom.: 23636 Cov.: 32 AF XY: 0.517 AC XY: 38422 AN XY: 74294

African (AFR) AF: 0.798 AC: 33081 AN: 41478

American (AMR) AF: 0.417 AC: 6375 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1686 AN: 3470

East Asian (EAS) AF: 0.169 AC: 875 AN: 5170

South Asian (SAS) AF: 0.427 AC: 2051 AN: 4808

European-Finnish (FIN) AF: 0.406 AC: 4272 AN: 10526

Middle Eastern (MID) AF: 0.627 AC: 183 AN: 292

European-Non Finnish (NFE) AF: 0.442 AC: 30040 AN: 67966

Other (OTH) AF: 0.540 AC: 1141 AN: 2114

Alfa AF: 0.514 Hom.: 18183

Bravo AF: 0.539

Asia WGS AF: 0.315 AC: 1100 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.79
PhyloP100		-0.36
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: rs875034; hg19: chr9-77357043;