chr9-74884880-T-C

Variant names:

• chr9-74884880-T-C
• rs11144134
• NM_017662.5:c.33+2944A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017662.5(TRPM6):​c.33+2944A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.06 in 152,200 control chromosomes in the GnomAD database, including 355 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 0.060 (355 hom., cov: 33)
• Consequence: TRPM6 NM_017662.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.32
• Publications: 26 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0842 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.33+2944A>G		intron	N/A	NP_060132.3
	TRPM6	NM_001177310.2		c.18+2751A>G		intron	N/A	NP_001170781.1
	TRPM6	NM_001177311.2		c.18+2351A>G		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.33+2944A>G		intron	N/A	ENSP00000354006.1
	TRPM6	ENST00000361255.7	TSL:1	c.18+2351A>G		intron	N/A	ENSP00000354962.3
	TRPM6	ENST00000449912.6	TSL:1	c.18+2751A>G		intron	N/A	ENSP00000396672.2

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9127 AN: 152082 Hom.: 356 Cov.: 33

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0808

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0398

Gnomad FIN AF: 0.0565

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0860

Gnomad OTH AF: 0.0753

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

GnomAD4 genome AF: 0.0600 AC: 9126 AN: 152200 Hom.: 355 Cov.: 33 AF XY: 0.0590 AC XY: 4393 AN XY: 74420

African (AFR) AF: 0.0191 AC: 792 AN: 41522

American (AMR) AF: 0.0806 AC: 1231 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 173 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.0400 AC: 193 AN: 4820

European-Finnish (FIN) AF: 0.0565 AC: 599 AN: 10596

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0860 AC: 5850 AN: 68020

Other (OTH) AF: 0.0745 AC: 157 AN: 2108

Alfa AF: 0.0772 Hom.: 276

Bravo AF: 0.0589

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.33
DANN	Benign	0.41
PhyloP100		-4.3
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: rs11144134; hg19: chr9-77499796;