Variant chr2-238848418-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_001271893.4(TWIST2):c.203G>T(p.Arg68Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TWIST2
NM_001271893.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.52

Variant links:

Genes affected

TWIST2 (HGNC:20670): (twist family bHLH transcription factor 2) The protein encoded by this gene is a basic helix-loop-helix type transcription factor and shares similarity with Twist. This protein may inhibit osteoblast maturation and maintain cells in a preosteoblast phenotype during osteoblast development. This gene may be upregulated in certain cancers. Mutations in this gene cause focal facial dermal dysplasia 3, Setleis type. Two transcript variants encoding the same protein have been found. [provided by RefSeq, Apr 2014]

TWIST2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a domain bHLH (size 51) in uniprot entity TWST2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001271893.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TWIST2	NM_001271893.4 linkuse as main transcript	c.203G>T	p.Arg68Leu	missense_variant	1/2	ENST00000612363.2
TWIST2	NM_057179.3 linkuse as main transcript	c.203G>T	p.Arg68Leu	missense_variant	1/2
TWIST2	XR_007069137.1 linkuse as main transcript	n.334G>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TWIST2	ENST00000612363.2 linkuse as main transcript	c.203G>T	p.Arg68Leu	missense_variant	1/2	1	NM_001271893.4	P1
TWIST2	ENST00000448943.2 linkuse as main transcript	c.203G>T	p.Arg68Leu	missense_variant	1/2	1		P1
TWIST2	ENST00000710607.1 linkuse as main transcript	c.203G>T	p.Arg68Leu	missense_variant	1/2			P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1387664

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684880

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

.;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

H;H

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-6.3

D;.

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.88

MutPred

0.81

Loss of MoRF binding (P = 0.0145);Loss of MoRF binding (P = 0.0145);

MVP

0.94

MPC

3.3

ClinPred

1.0

GERP RS

4.8

Varity_R

0.93

gMVP

0.98

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over