chr9-74800368-A-C

Variant names:

• chr9-74800368-A-C
• rs7859201
• NM_017662.5:c.2124T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017662.5(TRPM6):​c.2124T>G​(p.Leu708Leu) 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:7
• Conservation: PhyloP100: 0.390
• Publications: 20 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]

RN7SKP47 (HGNC:45771): (RN7SK pseudogene 47)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 367318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.2124T>G	p.Leu708Leu	synonymous	Exon 17 of 39	NP_060132.3
	TRPM6	NM_001177310.2		c.2109T>G	p.Leu703Leu	synonymous	Exon 17 of 39	NP_001170781.1	Q9BX84-2
	TRPM6	NM_001177311.2		c.2109T>G	p.Leu703Leu	synonymous	Exon 17 of 39	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.2124T>G	p.Leu708Leu	synonymous	Exon 17 of 39	ENSP00000354006.1	Q9BX84-1
	TRPM6	ENST00000361255.7	TSL:1	c.2109T>G	p.Leu703Leu	synonymous	Exon 17 of 39	ENSP00000354962.3	Q9BX84-3
	TRPM6	ENST00000449912.6	TSL:1	c.2109T>G	p.Leu703Leu	synonymous	Exon 17 of 39	ENSP00000396672.2	Q9BX84-2

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

GnomAD2 exomes AF: 0.397 AC: 99806 AN: 251414 AF XY: 0.397

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 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

African (AFR) AF: 0.681 AC: 22794 AN: 33480

American (AMR) AF: 0.297 AC: 13302 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 9579 AN: 26136

East Asian (EAS) AF: 0.368 AC: 14613 AN: 39700

South Asian (SAS) AF: 0.424 AC: 36572 AN: 86256

European-Finnish (FIN) AF: 0.411 AC: 21950 AN: 53416

Middle Eastern (MID) AF: 0.355 AC: 2045 AN: 5768

European-Non Finnish (NFE) AF: 0.380 AC: 422366 AN: 1111944

Other (OTH) AF: 0.395 AC: 23862 AN: 60396

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

African (AFR) AF: 0.668 AC: 27624 AN: 41340

American (AMR) AF: 0.353 AC: 5379 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1285 AN: 3468

East Asian (EAS) AF: 0.361 AC: 1857 AN: 5144

South Asian (SAS) AF: 0.412 AC: 1977 AN: 4798

European-Finnish (FIN) AF: 0.412 AC: 4327 AN: 10506

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.381 AC: 25871 AN: 67916

Other (OTH) AF: 0.403 AC: 847 AN: 2104

Alfa AF: 0.405 Hom.: 54335

Bravo AF: 0.463

Asia WGS AF: 0.388 AC: 1350 AN: 3478

EpiCase AF: 0.370

EpiControl AF: 0.376

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Intestinal hypomagnesemia 1 (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.1
DANN	Benign	0.65
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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