9-74887244-G-C

Position:

• chr9-74887244-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000361255.7(TRPM6):​c.5C>G​(p.Thr2Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. 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. T2I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRPM6 ENST00000361255.7 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10963535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM6	NM_017662.5	c.33+580C>G		intron_variant		ENST00000360774.6
TRPM6	NM_001177311.2	c.5C>G	p.Thr2Arg	missense_variant	1/39
TRPM6	NM_001177310.2	c.18+387C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM6	ENST00000361255.7	c.5C>G	p.Thr2Arg	missense_variant	1/39	1		A2
TRPM6	ENST00000360774.6	c.33+580C>G		intron_variant		1	NM_017662.5	P4
TRPM6	ENST00000449912.6	c.18+387C>G		intron_variant		1		A2
TRPM6	ENST00000359047.2	c.33+580C>G		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1118698 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 530356

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	10
DANN	Benign	0.97
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.055
Sift	Uncertain	0.015	D
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.067
MutPred		0.28		Gain of MoRF binding (P = 2e-04);
MVP		0.043
ClinPred		0.12	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;