NM_017662.5:c.3209+623G>A

Variant names:

• chr9-74781739-C-T
• rs6560408
• NM_017662.5:c.3209+623G>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.3209+623G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 151,772 control chromosomes in the GnomAD database, including 11,689 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 0.39 (11689 hom., cov: 30)
• Consequence: TRPM6 NM_017662.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.192
• Publications: 7 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=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.413 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.3209+623G>A		intron	N/A	NP_060132.3
	TRPM6	NM_001177310.2		c.3194+623G>A		intron	N/A	NP_001170781.1	Q9BX84-2
	TRPM6	NM_001177311.2		c.3194+623G>A		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.3209+623G>A		intron	N/A	ENSP00000354006.1	Q9BX84-1
	TRPM6	ENST00000361255.7	TSL:1	c.3194+623G>A		intron	N/A	ENSP00000354962.3	Q9BX84-3
	TRPM6	ENST00000449912.6	TSL:1	c.3194+623G>A		intron	N/A	ENSP00000396672.2	Q9BX84-2

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59142 AN: 151654 Hom.: 11690 Cov.: 30

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.439

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.418

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

GnomAD4 genome AF: 0.390 AC: 59170 AN: 151772 Hom.: 11689 Cov.: 30 AF XY: 0.387 AC XY: 28702 AN XY: 74150

African (AFR) AF: 0.394 AC: 16308 AN: 41350

American (AMR) AF: 0.330 AC: 5037 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1581 AN: 3464

East Asian (EAS) AF: 0.304 AC: 1562 AN: 5144

South Asian (SAS) AF: 0.429 AC: 2064 AN: 4816

European-Finnish (FIN) AF: 0.354 AC: 3729 AN: 10520

Middle Eastern (MID) AF: 0.441 AC: 127 AN: 288

European-Non Finnish (NFE) AF: 0.406 AC: 27557 AN: 67912

Other (OTH) AF: 0.415 AC: 875 AN: 2108

Alfa AF: 0.404 Hom.: 52273

Bravo AF: 0.386

Asia WGS AF: 0.361 AC: 1257 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.77
DANN	Benign	0.38
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs6560408; hg19: chr9-77396655;