9-74743052-C-T

Variant names:

• chr9-74743052-C-T
• rs877809
• NM_017662.5:c.5135-426G>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.5135-426G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 152,108 control chromosomes in the GnomAD database, including 7,214 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 0.23 (7214 hom., cov: 33)
• Consequence: TRPM6 NM_017662.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.341
• Publications: 6 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.553 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.5135-426G>A		intron	N/A	NP_060132.3
	TRPM6	NM_001177310.2		c.5120-426G>A		intron	N/A	NP_001170781.1	Q9BX84-2
	TRPM6	NM_001177311.2		c.5120-426G>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.5135-426G>A		intron	N/A	ENSP00000354006.1	Q9BX84-1
	TRPM6	ENST00000361255.7	TSL:1	c.5120-426G>A		intron	N/A	ENSP00000354962.3	Q9BX84-3
	TRPM6	ENST00000449912.6	TSL:1	c.5120-426G>A		intron	N/A	ENSP00000396672.2	Q9BX84-2

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34763 AN: 151990 Hom.: 7181 Cov.: 33

Gnomad AFR AF: 0.558

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.0939

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.0616

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0903

Gnomad OTH AF: 0.187

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

GnomAD4 genome AF: 0.229 AC: 34868 AN: 152108 Hom.: 7214 Cov.: 33 AF XY: 0.225 AC XY: 16713 AN XY: 74364

African (AFR) AF: 0.559 AC: 23159 AN: 41452

American (AMR) AF: 0.139 AC: 2124 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0939 AC: 326 AN: 3470

East Asian (EAS) AF: 0.159 AC: 822 AN: 5182

South Asian (SAS) AF: 0.234 AC: 1128 AN: 4812

European-Finnish (FIN) AF: 0.0616 AC: 654 AN: 10610

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.0903 AC: 6140 AN: 67982

Other (OTH) AF: 0.193 AC: 407 AN: 2114

Alfa AF: 0.131 Hom.: 7596

Bravo AF: 0.248

Asia WGS AF: 0.219 AC: 762 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.87
DANN	Benign	0.72
PhyloP100		-0.34
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: rs877809; hg19: chr9-77357968;