chr9-74745006-C-G

Variant names:

• chr9-74745006-C-G
• rs1327824
• NM_017662.5:c.5084-861G>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.5084-861G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0718 in 152,292 control chromosomes in the GnomAD database, including 430 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 0.072 (430 hom., cov: 32)
• Consequence: TRPM6 NM_017662.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.793
• 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.134 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM6	NM_017662.5	MANE Select	c.5084-861G>C		intron	N/A	NP_060132.3
	TRPM6	NM_001177310.2		c.5069-861G>C		intron	N/A	NP_001170781.1	Q9BX84-2
	TRPM6	NM_001177311.2		c.5069-861G>C		intron	N/A	NP_001170782.1	Q9BX84-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM6	ENST00000360774.6	TSL:1 MANE Select	c.5084-861G>C		intron	N/A	ENSP00000354006.1	Q9BX84-1
	TRPM6	ENST00000361255.7	TSL:1	c.5069-861G>C		intron	N/A	ENSP00000354962.3	Q9BX84-3
	TRPM6	ENST00000449912.6	TSL:1	c.5069-861G>C		intron	N/A	ENSP00000396672.2	Q9BX84-2

Frequencies

GnomAD3 genomes AF: 0.0718 AC: 10931 AN: 152174 Hom.: 432 Cov.: 32

Gnomad AFR AF: 0.0435

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0840

Gnomad ASJ AF: 0.0652

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.0750

Gnomad FIN AF: 0.0532

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0843

Gnomad OTH AF: 0.0568

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

GnomAD4 genome AF: 0.0718 AC: 10935 AN: 152292 Hom.: 430 Cov.: 32 AF XY: 0.0704 AC XY: 5242 AN XY: 74462

African (AFR) AF: 0.0435 AC: 1809 AN: 41572

American (AMR) AF: 0.0838 AC: 1283 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0652 AC: 226 AN: 3468

East Asian (EAS) AF: 0.143 AC: 739 AN: 5180

South Asian (SAS) AF: 0.0755 AC: 364 AN: 4822

European-Finnish (FIN) AF: 0.0532 AC: 564 AN: 10604

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0843 AC: 5731 AN: 68022

Other (OTH) AF: 0.0586 AC: 124 AN: 2116

Alfa AF: 0.0739 Hom.: 43

Bravo AF: 0.0741

Asia WGS AF: 0.0890 AC: 311 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.69
DANN	Benign	0.32
PhyloP100		-0.79
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: rs1327824; hg19: chr9-77359922;