9-74775929-G-T

Variant names:

• chr9-74775929-G-T
• rs1114167360
• NM_017662.5:c.3357C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_017662.5(TRPM6):​c.3357C>A​(p.Cys1119*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPM6 NM_017662.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.71
• 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-74775929-G-T is Pathogenic according to our data. Variant chr9-74775929-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 427900.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM6	NM_017662.5	MANE Select	c.3357C>A	p.Cys1119*	stop_gained	Exon 24 of 39	NP_060132.3
	TRPM6	NM_001177310.2		c.3342C>A	p.Cys1114*	stop_gained	Exon 24 of 39	NP_001170781.1
	TRPM6	NM_001177311.2		c.3342C>A	p.Cys1114*	stop_gained	Exon 24 of 39	NP_001170782.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM6	ENST00000360774.6	TSL:1 MANE Select	c.3357C>A	p.Cys1119*	stop_gained	Exon 24 of 39	ENSP00000354006.1
	TRPM6	ENST00000361255.7	TSL:1	c.3342C>A	p.Cys1114*	stop_gained	Exon 24 of 39	ENSP00000354962.3
	TRPM6	ENST00000449912.6	TSL:1	c.3342C>A	p.Cys1114*	stop_gained	Exon 24 of 39	ENSP00000396672.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intestinal hypomagnesemia 1 Pathogenic:1

Mar 03, 2017

Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Benign	0.14
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		1.7
Vest4		0.91
GERP RS		3.1
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1114167360; hg19: chr9-77390845;