rs7859201

chr9-74800368-A-Cchr9-74800368-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017662.5(TRPM6):c.2124T>G(p.Leu708=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,613,550 control chromosomes in the GnomAD database, including 129,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17381 hom., cov: 30)
  • Exomes 𝑓: 0.39 (112231 hom.)
• Consequence: TRPM6 NM_017662.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.390

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 9-74800368-A-C is Benign according to our data. Variant chr9-74800368-A-C is described in ClinVar as [Benign]. Clinvar id is 367318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-74800368-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM6	NM_017662.5	c.2124T>G	p.Leu708=	synonymous_variant	17/39	ENST00000360774.6
TRPM6	NM_001177310.2	c.2109T>G	p.Leu703=	synonymous_variant	17/39
TRPM6	NM_001177311.2	c.2109T>G	p.Leu703=	synonymous_variant	17/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM6	ENST00000360774.6	c.2124T>G	p.Leu708=	synonymous_variant	17/39	1	NM_017662.5	P4
TRPM6	ENST00000361255.7	c.2109T>G	p.Leu703=	synonymous_variant	17/39	1		A2
TRPM6	ENST00000449912.6	c.2109T>G	p.Leu703=	synonymous_variant	17/39	1		A2

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69495 AN: 151614 Hom.: 17356 Cov.: 30

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.402

GnomAD3 exomes AF: 0.397 AC: 99806 AN: 251414 Hom.: 20847 AF XY: 0.397 AC XY: 53947 AN XY: 135884

Gnomad AFR exome AF: 0.681

Gnomad AMR exome AF: 0.291

Gnomad ASJ exome AF: 0.367

Gnomad EAS exome AF: 0.366

Gnomad SAS exome AF: 0.421

Gnomad FIN exome AF: 0.408

Gnomad NFE exome AF: 0.388

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.388 AC: 567083 AN: 1461818 Hom.: 112231 Cov.: 48 AF XY: 0.388 AC XY: 282456 AN XY: 727214

Gnomad4 AFR exome AF: 0.681

Gnomad4 AMR exome AF: 0.297

Gnomad4 ASJ exome AF: 0.367

Gnomad4 EAS exome AF: 0.368

Gnomad4 SAS exome AF: 0.424

Gnomad4 FIN exome AF: 0.411

Gnomad4 NFE exome AF: 0.380

Gnomad4 OTH exome AF: 0.395

GnomAD4 genome AF: 0.459 AC: 69580 AN: 151732 Hom.: 17381 Cov.: 30 AF XY: 0.456 AC XY: 33793 AN XY: 74130

Gnomad4 AFR AF: 0.668

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.371

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.381

Gnomad4 OTH AF: 0.403

Alfa AF: 0.393 Hom.: 23948

Bravo AF: 0.463

Asia WGS AF: 0.388 AC: 1350 AN: 3478

EpiCase AF: 0.370

EpiControl AF: 0.376

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Intestinal hypomagnesemia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	8.1
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7859201; hg19: chr9-77415284; COSMIC: COSV62502563; COSMIC: COSV62502563;