9-74852321-A-G

Variant names:

• chr9-74852321-A-G
• rs10869447
• NM_017662.5:c.152+3206T>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.152+3206T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 150,978 control chromosomes in the GnomAD database, including 8,504 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 0.31 (8504 hom., cov: 29)
• Consequence: TRPM6 NM_017662.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.604
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.487 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.152+3206T>C		intron	N/A	NP_060132.3
	TRPM6	NM_001177310.2		c.137+3206T>C		intron	N/A	NP_001170781.1
	TRPM6	NM_001177311.2		c.137+3206T>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.152+3206T>C		intron	N/A	ENSP00000354006.1
	TRPM6	ENST00000361255.7	TSL:1	c.137+3206T>C		intron	N/A	ENSP00000354962.3
	TRPM6	ENST00000449912.6	TSL:1	c.137+3206T>C		intron	N/A	ENSP00000396672.2

Frequencies

GnomAD3 genomes AF: 0.311 AC: 46846 AN: 150870 Hom.: 8504 Cov.: 29

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.311

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

GnomAD4 genome AF: 0.310 AC: 46865 AN: 150978 Hom.: 8504 Cov.: 29 AF XY: 0.317 AC XY: 23392 AN XY: 73696

African (AFR) AF: 0.115 AC: 4745 AN: 41246

American (AMR) AF: 0.386 AC: 5871 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1115 AN: 3458

East Asian (EAS) AF: 0.504 AC: 2574 AN: 5110

South Asian (SAS) AF: 0.447 AC: 2129 AN: 4768

European-Finnish (FIN) AF: 0.418 AC: 4251 AN: 10176

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.370 AC: 25027 AN: 67714

Other (OTH) AF: 0.313 AC: 656 AN: 2098

Alfa AF: 0.229 Hom.: 615

Bravo AF: 0.297

Asia WGS AF: 0.447 AC: 1554 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.4
DANN	Benign	0.63
PhyloP100		-0.60
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: rs10869447; hg19: chr9-77467237;