Genetic Variant TRPM7:p.Gly1642Gly (chr15-50574945-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BA1

The NM_017672.6(TRPM7):c.4926G>A(p.Gly1642Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 1,613,802 control chromosomes in the GnomAD database, including 2,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. G1642G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.080 ( 808 hom., cov: 32)

Exomes 𝑓: 0.044 ( 2039 hom. )

Consequence

TRPM7
NM_017672.6 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.0480

Publications

11 publications found

Variant links:

Genes affected

TRPM7 (HGNC:17994): (transient receptor potential cation channel subfamily M member 7) This gene belongs to the melastatin subfamily of transient receptor potential family of ion channels. The protein encoded by this gene is both an ion channel and a serine/threonine protein kinase. The kinase activity is essential for the ion channel function, which serves to increase intracellular calcium levels and to help regulate magnesium ion homeostasis. The encoded protein is involved in cytoskeletal organization, cell adhesion, cell migration and organogenesis. Defects in this gene are a cause of amyotrophic lateral sclerosis-parkinsonism/dementia complex of Guam. The gene may also be associated with defects of cardiac function. [provided by RefSeq, Aug 2017]

TRPM7 Gene-Disease associations (from GenCC):

hypomagnesemia, seizures, and intellectual disability
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
macrothrombocytopenia, isolated
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen
autosomal dominant macrothrombocytopenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
amyotrophic lateral sclerosis-parkinsonism-dementia complex
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

TRPM7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 15-50574945-C-T is Benign according to our data. Variant chr15-50574945-C-T is described in ClinVar as Benign. ClinVar VariationId is 3056472.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-0.048 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017672.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPM7	NM_017672.6	MANE Select	c.4926G>A	p.Gly1642Gly	synonymous	Exon 34 of 39	NP_060142.3
TRPM7	NM_001301212.2		c.4923G>A	p.Gly1641Gly	synonymous	Exon 34 of 39	NP_001288141.1	H0YLN8
TRPM7	NR_149152.2		n.5140G>A		non_coding_transcript_exon	Exon 34 of 39

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPM7	ENST00000646667.1	MANE Select	c.4926G>A	p.Gly1642Gly	synonymous	Exon 34 of 39	ENSP00000495860.1	Q96QT4
TRPM7	ENST00000560955.5	TSL:1	c.4923G>A	p.Gly1641Gly	synonymous	Exon 34 of 39	ENSP00000453277.1	H0YLN8
TRPM7	ENST00000561267.5	TSL:3	c.63G>A	p.Gly21Gly	synonymous	Exon 1 of 6	ENSP00000454066.1	H0YNM0

Frequencies

GnomAD3 genomes

AF:

0.0801

AC:

12179

AN:

152032

Hom.:

808

Cov.:

show subpopulations

Gnomad AFR

AF:

0.184

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0617

Gnomad ASJ

AF:

0.0899

Gnomad EAS

AF:

0.00366

Gnomad SAS

AF:

0.0441

Gnomad FIN

AF:

0.0135

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0404

Gnomad OTH

AF:

0.0796

GnomAD2 exomes

AF:

0.0484

AC:

12062

AN:

249418

AF XY:

0.0478

show subpopulations

Gnomad AFR exome

AF:

0.189

Gnomad AMR exome

AF:

0.0386

Gnomad ASJ exome

AF:

0.0946

Gnomad EAS exome

AF:

0.00206

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.0429

Gnomad OTH exome

AF:

0.0507

GnomAD4 exome

AF:

0.0439

AC:

64116

AN:

1461652

Hom.:

2039

Cov.:

AF XY:

0.0440

AC XY:

32024

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.191

AC:

6385

AN:

33468

American (AMR)

AF:

0.0409

AC:

1828

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0960

AC:

2509

AN:

26132

East Asian (EAS)

AF:

0.000630

AC:

AN:

39686

South Asian (SAS)

AF:

0.0476

AC:

4109

AN:

86248

European-Finnish (FIN)

AF:

0.0119

AC:

636

AN:

53412

Middle Eastern (MID)

AF:

0.0907

AC:

523

AN:

5766

European-Non Finnish (NFE)

AF:

0.0404

AC:

44881

AN:

1111832

Other (OTH)

AF:

0.0533

AC:

3220

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

3146

6292

9437

12583

15729

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1764

3528

5292

7056

8820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0801

AC:

12188

AN:

152150

Hom.:

808

Cov.:

AF XY:

0.0783

AC XY:

5822

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.184

AC:

7611

AN:

41474

American (AMR)

AF:

0.0616

AC:

941

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0899

AC:

312

AN:

3470

East Asian (EAS)

AF:

0.00309

AC:

AN:

5186

South Asian (SAS)

AF:

0.0439

AC:

212

AN:

4824

European-Finnish (FIN)

AF:

0.0135

AC:

143

AN:

10598

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0404

AC:

2746

AN:

68004

Other (OTH)

AF:

0.0787

AC:

166

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

547

1095

1642

2190

2737

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0613

Hom.:

1282

Bravo

AF:

0.0872

Asia WGS

AF:

0.0360

AC:

128

AN:

3478

EpiCase

AF:

0.0496

EpiControl

AF:

0.0526

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

TRPM7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

4.5

(source)

DANN

Benign

0.65

PhyloP100

-0.048

PromoterAI

0.010

Neutral

(source)

Mutation Taster

=70/30

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over