Variant 1-205241581-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014858.4(TMCC2):c.284G>A(p.Arg95Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000633 in 1,613,794 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 1 hom. )

Consequence

TMCC2
NM_014858.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.86

Variant links:

Genes affected

TMCC2 (HGNC:24239): (transmembrane and coiled-coil domain family 2) Involved in amyloid precursor protein metabolic process. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

TMCC2 links:

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ACMG classification

Classification made for transcript

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=0.11608127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMCC2	NM_014858.4 link	c.284G>A	p.Arg95Gln	missense_variant	2/5	ENST00000358024.8	NP_055673.2	O75069-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMCC2	ENST00000358024.8 link	c.284G>A	p.Arg95Gln	missense_variant	2/5	1	NM_014858.4	ENSP00000350718.3	O75069-1
TMCC2	ENST00000545499.5 link	c.50G>A	p.Arg17Gln	missense_variant	2/5	2		ENSP00000437943.1	O75069-2
TMCC2	ENST00000495538.5 link	n.515G>A		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000419

AC:

105

AN:

250712

Hom.:

AF XY:

0.000479

AC XY:

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000795

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000660

AC:

965

AN:

1461690

Hom.:

Cov.:

AF XY:

0.000660

AC XY:

480

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000338

Gnomad4 NFE exome

AF:

0.000817

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000375

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000668

Hom.:

Bravo

AF:

0.000495

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000445

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2024

The c.284G>A (p.R95Q) alteration is located in exon 2 (coding exon 2) of the TMCC2 gene. This alteration results from a G to A substitution at nucleotide position 284, causing the arginine (R) at amino acid position 95 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.021

T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

D;D

M_CAP

Benign

0.057

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.6

L;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.24

N;N

REVEL

Benign

0.15

Sift

Benign

0.030

D;T

Sift4G

Benign

0.48

T;T

Polyphen

1.0

D;.

Vest4

0.48

MVP

0.55

MPC

1.6

ClinPred

0.057

GERP RS

4.8

Varity_R

0.11

gMVP

0.45

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over