rs1333342

Variant names:

• chr9-74887244-G-A
• rs1333342
• ENST00000361255.7:c.5C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-74887244-G-A
• chr9-74887244-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 14/18 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0270
• Publications: 16 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 -20 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 VariationId is 1263183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
TRPM6	NM_017662.5	c.33+580C>T		intron_variant	Intron 1 of 38	ENST00000360774.6	NP_060132.3
TRPM6	NM_001177311.2	c.5C>T	p.Thr2Ile	missense_variant	Exon 1 of 39		NP_001170782.1
TRPM6	NM_001177310.2	c.18+387C>T		intron_variant	Intron 1 of 38		NP_001170781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM6	ENST00000360774.6	c.33+580C>T		intron_variant	Intron 1 of 38	1	NM_017662.5	ENSP00000354006.1

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

GnomAD2 exomes AF: 0.414 AC: 7760 AN: 18738 AF XY: 0.419

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 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

African (AFR) AF: 0.134 AC: 3233 AN: 24044

American (AMR) AF: 0.501 AC: 5888 AN: 11746

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 5429 AN: 14924

East Asian (EAS) AF: 0.474 AC: 13638 AN: 28742

South Asian (SAS) AF: 0.463 AC: 12080 AN: 26084

European-Finnish (FIN) AF: 0.480 AC: 10957 AN: 22810

Middle Eastern (MID) AF: 0.397 AC: 1847 AN: 4652

European-Non Finnish (NFE) AF: 0.440 AC: 413191 AN: 939170

Other (OTH) AF: 0.421 AC: 19198 AN: 45558

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

African (AFR) AF: 0.150 AC: 6252 AN: 41546

American (AMR) AF: 0.462 AC: 7067 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1278 AN: 3472

East Asian (EAS) AF: 0.500 AC: 2585 AN: 5170

South Asian (SAS) AF: 0.479 AC: 2309 AN: 4820

European-Finnish (FIN) AF: 0.467 AC: 4940 AN: 10580

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30334 AN: 67950

Other (OTH) AF: 0.374 AC: 788 AN: 2108

Alfa AF: 0.411 Hom.: 41168

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
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
PhyloP100		0.027
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
PromoterAI		-0.030	Neutral
Mutation Taster		=97/3	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: rs1333342; hg19: chr9-77502160; COSMIC: COSV62511715;