9-74827700-C-T

Variant names:

• chr9-74827700-C-T
• rs7045949
• NM_017662.5:c.841+78G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017662.5(TRPM6):​c.841+78G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 1,483,244 control chromosomes in the GnomAD database, including 255,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27311 hom., cov: 29)
  • Exomes 𝑓: 0.58 (228365 hom.)
• Consequence: TRPM6 NM_017662.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.91
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 9-74827700-C-T is Benign according to our data. Variant chr9-74827700-C-T is described in ClinVar as Benign. ClinVar VariationId is 1236618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.774 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.841+78G>A		intron	N/A	NP_060132.3
	TRPM6	NM_001177310.2		c.826+78G>A		intron	N/A	NP_001170781.1
	TRPM6	NM_001177311.2		c.826+78G>A		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.841+78G>A		intron	N/A	ENSP00000354006.1
	TRPM6	ENST00000361255.7	TSL:1	c.826+78G>A		intron	N/A	ENSP00000354962.3
	TRPM6	ENST00000449912.6	TSL:1	c.826+78G>A		intron	N/A	ENSP00000396672.2

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90327 AN: 151362 Hom.: 27255 Cov.: 29

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.620

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.795

Gnomad SAS AF: 0.706

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.554

GnomAD2 exomes AF: 0.614 AC: 152526 AN: 248538 AF XY: 0.613

Gnomad AFR exome AF: 0.654

Gnomad AMR exome AF: 0.659

Gnomad ASJ exome AF: 0.481

Gnomad EAS exome AF: 0.815

Gnomad FIN exome AF: 0.540

Gnomad NFE exome AF: 0.563

Gnomad OTH exome AF: 0.578

GnomAD4 exome AF: 0.583 AC: 775842 AN: 1331764 Hom.: 228365 Cov.: 20 AF XY: 0.585 AC XY: 391806 AN XY: 669286

African (AFR) AF: 0.646 AC: 19932 AN: 30858

American (AMR) AF: 0.652 AC: 28968 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 12380 AN: 25370

East Asian (EAS) AF: 0.793 AC: 30999 AN: 39090

South Asian (SAS) AF: 0.706 AC: 59044 AN: 83646

European-Finnish (FIN) AF: 0.550 AC: 29361 AN: 53338

Middle Eastern (MID) AF: 0.499 AC: 2755 AN: 5520

European-Non Finnish (NFE) AF: 0.564 AC: 559932 AN: 993278

Other (OTH) AF: 0.578 AC: 32471 AN: 56212

GnomAD4 genome AF: 0.597 AC: 90450 AN: 151480 Hom.: 27311 Cov.: 29 AF XY: 0.598 AC XY: 44238 AN XY: 73976

African (AFR) AF: 0.649 AC: 26785 AN: 41294

American (AMR) AF: 0.582 AC: 8880 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 1683 AN: 3472

East Asian (EAS) AF: 0.795 AC: 4004 AN: 5038

South Asian (SAS) AF: 0.707 AC: 3385 AN: 4790

European-Finnish (FIN) AF: 0.539 AC: 5663 AN: 10508

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.563 AC: 38181 AN: 67832

Other (OTH) AF: 0.560 AC: 1175 AN: 2100

Alfa AF: 0.572 Hom.: 103733

Bravo AF: 0.602

Asia WGS AF: 0.723 AC: 2514 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.13
DANN	Benign	0.38
PhyloP100		-2.9
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: rs7045949; hg19: chr9-77442616; COSMIC: COSV62507537;