9-74755855-C-T

Variant names:

• chr9-74755855-C-T
• rs2769195
• NM_017662.5:c.4786-382G>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.4786-382G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 152,016 control chromosomes in the GnomAD database, including 32,568 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 0.64 (32568 hom., cov: 31)
• Consequence: TRPM6 NM_017662.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• Publications: 8 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM6	NM_017662.5	c.4786-382G>A		intron_variant	Intron 27 of 38	ENST00000360774.6	NP_060132.3
TRPM6	NM_001177310.2	c.4771-382G>A		intron_variant	Intron 27 of 38		NP_001170781.1
TRPM6	NM_001177311.2	c.4771-382G>A		intron_variant	Intron 27 of 38		NP_001170782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM6	ENST00000360774.6	c.4786-382G>A		intron_variant	Intron 27 of 38	1	NM_017662.5	ENSP00000354006.1
TRPM6	ENST00000361255.7	c.4771-382G>A		intron_variant	Intron 27 of 38	1		ENSP00000354962.3
TRPM6	ENST00000449912.6	c.4771-382G>A		intron_variant	Intron 27 of 38	1		ENSP00000396672.2
TRPM6	ENST00000715553.1	n.4786-382G>A		intron_variant	Intron 27 of 39			ENSP00000520473.1

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96920 AN: 151898 Hom.: 32523 Cov.: 31

Gnomad AFR AF: 0.858

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.642

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

GnomAD4 genome AF: 0.638 AC: 97020 AN: 152016 Hom.: 32568 Cov.: 31 AF XY: 0.629 AC XY: 46695 AN XY: 74294

African (AFR) AF: 0.858 AC: 35602 AN: 41502

American (AMR) AF: 0.532 AC: 8126 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 2053 AN: 3472

East Asian (EAS) AF: 0.486 AC: 2505 AN: 5156

South Asian (SAS) AF: 0.604 AC: 2903 AN: 4808

European-Finnish (FIN) AF: 0.469 AC: 4941 AN: 10524

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.571 AC: 38795 AN: 67958

Other (OTH) AF: 0.644 AC: 1357 AN: 2108

Alfa AF: 0.582 Hom.: 16073

Bravo AF: 0.653

Asia WGS AF: 0.545 AC: 1898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.5
DANN	Benign	0.66
PhyloP100		1.3
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: rs2769195; hg19: chr9-77370771;