NM_017662.5:c.1444-437T>C

Variant names:

• chr9-74811305-A-G
• rs1012710
• NM_017662.5:c.1444-437T>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.1444-437T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 152,142 control chromosomes in the GnomAD database, including 6,852 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 0.27 (6852 hom., cov: 33)
• Consequence: TRPM6 NM_017662.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0350
• 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=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 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.1444-437T>C		intron	N/A	NP_060132.3
	TRPM6	NM_001177310.2		c.1429-437T>C		intron	N/A	NP_001170781.1
	TRPM6	NM_001177311.2		c.1429-437T>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.1444-437T>C		intron	N/A	ENSP00000354006.1
	TRPM6	ENST00000361255.7	TSL:1	c.1429-437T>C		intron	N/A	ENSP00000354962.3
	TRPM6	ENST00000449912.6	TSL:1	c.1429-437T>C		intron	N/A	ENSP00000396672.2

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40775 AN: 152024 Hom.: 6847 Cov.: 33

Gnomad AFR AF: 0.0891

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.277

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

GnomAD4 genome AF: 0.268 AC: 40800 AN: 152142 Hom.: 6852 Cov.: 33 AF XY: 0.277 AC XY: 20582 AN XY: 74380

African (AFR) AF: 0.0890 AC: 3699 AN: 41544

American (AMR) AF: 0.346 AC: 5291 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1008 AN: 3468

East Asian (EAS) AF: 0.671 AC: 3473 AN: 5176

South Asian (SAS) AF: 0.446 AC: 2150 AN: 4826

European-Finnish (FIN) AF: 0.343 AC: 3621 AN: 10570

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.304 AC: 20663 AN: 67968

Other (OTH) AF: 0.279 AC: 590 AN: 2114

Alfa AF: 0.300 Hom.: 3842

Bravo AF: 0.260

Asia WGS AF: 0.509 AC: 1770 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.0
DANN	Benign	0.88
PhyloP100		-0.035
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: rs1012710; hg19: chr9-77426221;