Variant chr15-51798208-C-G 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_014548.4(TMOD2):c.744C>G(p.Asp248Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,446,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

TMOD2
NM_014548.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.366

Variant links:

Genes affected

TMOD2 (HGNC:11872): (tropomodulin 2) This gene encodes a neuronal-specific member of the tropomodulin family of actin-regulatory proteins. The encoded protein caps the pointed end of actin filaments preventing both elongation and depolymerization. The capping activity of this protein is dependent on its association with tropomyosin. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Dec 2008]

TMOD2 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=0.081066936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMOD2	NM_014548.4 linkuse as main transcript	c.744C>G	p.Asp248Glu	missense_variant	8/10	ENST00000249700.9	NP_055363.1
TMOD2	NM_001142885.2 linkuse as main transcript	c.636C>G	p.Asp212Glu	missense_variant	7/9		NP_001136357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMOD2	ENST00000249700.9 linkuse as main transcript	c.744C>G	p.Asp248Glu	missense_variant	8/10	1	NM_014548.4	ENSP00000249700	P1	Q9NZR1-1
TMOD2	ENST00000435126.6 linkuse as main transcript	c.636C>G	p.Asp212Glu	missense_variant	7/9	2		ENSP00000404590		Q9NZR1-2
TMOD2	ENST00000539962.6 linkuse as main transcript	c.612C>G	p.Asp204Glu	missense_variant	9/11	2		ENSP00000437743
TMOD2	ENST00000561407.1 linkuse as main transcript	c.21C>G	p.Asp7Glu	missense_variant, NMD_transcript_variant	2/5	5		ENSP00000453524

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000170

AC:

AN:

235666

Hom.:

AF XY:

0.0000236

AC XY:

AN XY:

127348

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000111

AC:

AN:

1446144

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

718966

show subpopulations

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:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

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

Oct 26, 2021

The c.744C>G (p.D248E) alteration is located in exon 8 (coding exon 7) of the TMOD2 gene. This alteration results from a C to G substitution at nucleotide position 744, causing the aspartic acid (D) at amino acid position 248 to be replaced by a glutamic acid (E). 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

Benign

0.098

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Benign

0.11

T;T;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.74

T;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.081

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.15

N;.;.

MutationTaster

Benign

0.88

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.010

N;N;N

REVEL

Benign

0.26

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.028

B;.;B

Vest4

0.14

MutPred

0.34

Loss of helix (P = 0.1299);.;.;

MVP

0.50

MPC

0.034

ClinPred

0.019

GERP RS

0.046

Varity_R

0.087

gMVP

0.29

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