rs1333342

chr9-74887244-G-Achr9-74887244-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000361255.7(TRPM6):c.5C>T(p.Thr2Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 1,269,866 control chromosomes in the GnomAD database, including 119,750 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (11967 hom., cov: 33)
  • Exomes 𝑓: 0.43 (107783 hom.)
• Consequence: TRPM6 ENST00000361255.7 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0270

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.001161E-5).
• BP6: Variant 9-74887244-G-A is Benign according to our data. Variant chr9-74887244-G-A is described in ClinVar as [Benign]. Clinvar id is 1263183.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM6	NM_017662.5	c.33+580C>T		intron_variant		ENST00000360774.6
TRPM6	NM_001177311.2	c.5C>T	p.Thr2Ile	missense_variant	1/39
TRPM6	NM_001177310.2	c.18+387C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM6	ENST00000361255.7	c.5C>T	p.Thr2Ile	missense_variant	1/39	1		A2
TRPM6	ENST00000360774.6	c.33+580C>T		intron_variant		1	NM_017662.5	P4
TRPM6	ENST00000449912.6	c.18+387C>T		intron_variant		1		A2
TRPM6	ENST00000359047.2	c.33+580C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.369 AC: 56153 AN: 152018 Hom.: 11963 Cov.: 33

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.372

GnomAD3 exomes AF: 0.414 AC: 7760 AN: 18738 Hom.: 1773 AF XY: 0.419 AC XY: 4175 AN XY: 9962

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.490

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.458

Gnomad SAS exome AF: 0.456

Gnomad FIN exome AF: 0.444

Gnomad NFE exome AF: 0.417

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.434 AC: 485461 AN: 1117730 Hom.: 107783 Cov.: 33 AF XY: 0.435 AC XY: 230459 AN XY: 529926

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.501

Gnomad4 ASJ exome AF: 0.364

Gnomad4 EAS exome AF: 0.474

Gnomad4 SAS exome AF: 0.463

Gnomad4 FIN exome AF: 0.480

Gnomad4 NFE exome AF: 0.440

Gnomad4 OTH exome AF: 0.421

GnomAD4 genome AF: 0.369 AC: 56172 AN: 152136 Hom.: 11967 Cov.: 33 AF XY: 0.376 AC XY: 27946 AN XY: 74386

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.462

Gnomad4 ASJ AF: 0.368

Gnomad4 EAS AF: 0.500

Gnomad4 SAS AF: 0.479

Gnomad4 FIN AF: 0.467

Gnomad4 NFE AF: 0.446

Gnomad4 OTH AF: 0.374

Alfa AF: 0.425 Hom.: 26888

Bravo AF: 0.355

TwinsUK AF: 0.450 AC: 1669

ALSPAC AF: 0.441 AC: 1700

ExAC AF: 0.197 AC: 1133

Asia WGS AF: 0.461 AC: 1606 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	11
Dann	Benign	0.95
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.000040	T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.010
Sift	Uncertain	0.023	D
Sift4G	Benign	0.27	T
Polyphen		0.26	B
Vest4		0.037
ClinPred		0.0050	T
GERP RS		1.9

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: rs1333342; hg19: chr9-77502160; COSMIC: COSV62511715;