9-74792666-AT-GA

Variant names:

• chr9-74792666-AT-GA
• NM_017662.5:c.2495_2496delATinsTC
• TRPM6 p.Tyr832Phe

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM5

The NM_017662.5(TRPM6):​c.2495_2496delATinsTC​(p.Tyr832Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y832C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPM6 NM_017662.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.05
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-74792667-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 403726.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2495_2496delATinsTC	p.Tyr832Phe	missense	N/A	NP_060132.3
	TRPM6	NM_001177310.2		c.2480_2481delATinsTC	p.Tyr827Phe	missense	N/A	NP_001170781.1	Q9BX84-2
	TRPM6	NM_001177311.2		c.2480_2481delATinsTC	p.Tyr827Phe	missense	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.2495_2496delATinsTC	p.Tyr832Phe	missense	N/A	ENSP00000354006.1	Q9BX84-1
	TRPM6	ENST00000361255.7	TSL:1	c.2480_2481delATinsTC	p.Tyr827Phe	missense	N/A	ENSP00000354962.3	Q9BX84-3
	TRPM6	ENST00000449912.6	TSL:1	c.2480_2481delATinsTC	p.Tyr827Phe	missense	N/A	ENSP00000396672.2	Q9BX84-2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-77407582;