9-74723453-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_017662.5(TRPM6):c.*1160C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 150,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRPM6 NM_017662.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.282

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-74723453-G-A is Benign according to our data. Variant chr9-74723453-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 913247.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00117 (177/150752) while in subpopulation NFE AF= 0.00192 (130/67838). AF 95% confidence interval is 0.00165. There are 1 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM6	NM_017662.5	c.*1160C>T		3_prime_UTR_variant	39/39	ENST00000360774.6
TRPM6	NM_001177310.2	c.*1160C>T		3_prime_UTR_variant	39/39
TRPM6	NM_001177311.2	c.*1160C>T		3_prime_UTR_variant	39/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM6	ENST00000360774.6	c.*1160C>T		3_prime_UTR_variant	39/39	1	NM_017662.5	P4
TRPM6	ENST00000361255.7	c.*1160C>T		3_prime_UTR_variant	39/39	1		A2
TRPM6	ENST00000449912.6	c.*1160C>T		3_prime_UTR_variant	39/39	1		A2

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 177 AN: 150648 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000465

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000797

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00189

Gnomad FIN AF: 0.0000977

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00192

Gnomad OTH AF: 0.00290

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.00117 AC: 177 AN: 150752 Hom.: 1 Cov.: 31 AF XY: 0.00114 AC XY: 84 AN XY: 73554

Gnomad4 AFR AF: 0.000464

Gnomad4 AMR AF: 0.000796

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00189

Gnomad4 FIN AF: 0.0000977

Gnomad4 NFE AF: 0.00192

Gnomad4 OTH AF: 0.00287

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00134

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intestinal hypomagnesemia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	7.9
Dann	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs563649179; hg19: chr9-77338369;