chr9-74833606-T-G

Variant names:

• chr9-74833606-T-G
• rs11144108
• NM_017662.5:c.669+392A>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.669+392A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 152,106 control chromosomes in the GnomAD database, including 7,988 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 0.30 (7988 hom., cov: 33)
• Consequence: TRPM6 NM_017662.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.171
• Publications: 6 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 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.669+392A>C		intron	N/A	NP_060132.3
	TRPM6	NM_001177310.2		c.654+392A>C		intron	N/A	NP_001170781.1
	TRPM6	NM_001177311.2		c.654+392A>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.669+392A>C		intron	N/A	ENSP00000354006.1
	TRPM6	ENST00000361255.7	TSL:1	c.654+392A>C		intron	N/A	ENSP00000354962.3
	TRPM6	ENST00000449912.6	TSL:1	c.654+392A>C		intron	N/A	ENSP00000396672.2

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45067 AN: 151988 Hom.: 7988 Cov.: 33

Gnomad AFR AF: 0.0976

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.298

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

GnomAD4 genome AF: 0.296 AC: 45083 AN: 152106 Hom.: 7988 Cov.: 33 AF XY: 0.303 AC XY: 22554 AN XY: 74340

African (AFR) AF: 0.0975 AC: 4051 AN: 41546

American (AMR) AF: 0.374 AC: 5711 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1049 AN: 3464

East Asian (EAS) AF: 0.521 AC: 2684 AN: 5156

South Asian (SAS) AF: 0.453 AC: 2188 AN: 4826

European-Finnish (FIN) AF: 0.393 AC: 4145 AN: 10560

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.356 AC: 24214 AN: 67972

Other (OTH) AF: 0.300 AC: 635 AN: 2116

Alfa AF: 0.329 Hom.: 7066

Bravo AF: 0.283

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.0
DANN	Benign	0.49
PhyloP100		-0.17
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: rs11144108; hg19: chr9-77448522;