9-74887244-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001177311.2(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. 16/19 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 NM_001177311.2 missense
• Clinical Significance: Not reported in ClinVar
• 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177311.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM6	NM_017662.5	MANE Select	c.33+580C>G		intron	N/A	NP_060132.3
	TRPM6	NM_001177311.2		c.5C>G	p.Thr2Arg	missense	Exon 1 of 39	NP_001170782.1	Q9BX84-3
	TRPM6	NM_001177310.2		c.18+387C>G		intron	N/A	NP_001170781.1	Q9BX84-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM6	ENST00000361255.7	TSL:1	c.5C>G	p.Thr2Arg	missense	Exon 1 of 39	ENSP00000354962.3	Q9BX84-3
	TRPM6	ENST00000360774.6	TSL:1 MANE Select	c.33+580C>G		intron	N/A	ENSP00000354006.1	Q9BX84-1
	TRPM6	ENST00000449912.6	TSL:1	c.18+387C>G		intron	N/A	ENSP00000396672.2	Q9BX84-2

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

African (AFR) AF: 0.00 AC: 0 AN: 24052

American (AMR) AF: 0.00 AC: 0 AN: 11750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14940

East Asian (EAS) AF: 0.00 AC: 0 AN: 28758

South Asian (SAS) AF: 0.00 AC: 0 AN: 26112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4654

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 940028

Other (OTH) AF: 0.00 AC: 0 AN: 45588

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 41168

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
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
PhyloP100		0.027
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
PromoterAI		-0.063	Neutral
Mutation Taster		=96/4	polymorphism

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;