Variant chr2-238848571-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_001271893.4(TWIST2):c.356A>G(p.Gln119Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,582,700 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

TWIST2
NM_001271893.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.92

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a chain Twist-related protein 2 (size 159) in uniprot entity TWST2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001271893.4

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TWIST2	NM_001271893.4 linkuse as main transcript	c.356A>G	p.Gln119Arg	missense_variant	1/2	ENST00000612363.2
TWIST2	NM_057179.3 linkuse as main transcript	c.356A>G	p.Gln119Arg	missense_variant	1/2
TWIST2	XR_007069137.1 linkuse as main transcript	n.487A>G		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.356A>G	p.Gln119Arg	missense_variant	1/2	1	NM_001271893.4	P1
TWIST2	ENST00000448943.2 linkuse as main transcript	c.356A>G	p.Gln119Arg	missense_variant	1/2	1		P1
TWIST2	ENST00000710607.1 linkuse as main transcript	c.356A>G	p.Gln119Arg	missense_variant	1/2			P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1430504

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

709136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000306

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

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The c.356A>G (p.Q119R) alteration is located in exon 1 (coding exon 1) of the TWIST2 gene. This alteration results from a A to G substitution at nucleotide position 356, causing the glutamine (Q) at amino acid position 119 to be replaced by an arginine (R). 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

0.37

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Benign

0.86

DEOGEN2

Uncertain

0.49

T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.098

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.66

.;T

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Pathogenic

0.82

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.8

D;.

REVEL

Uncertain

0.54

Sift

Benign

0.087

T;.

Sift4G

Benign

0.19

T;T

Polyphen

0.024

B;B

Vest4

0.68

MutPred

0.26

Gain of MoRF binding (P = 0.0349);Gain of MoRF binding (P = 0.0349);

MVP

0.96

MPC

1.7

ClinPred

0.52

GERP RS

3.8

Varity_R

0.41

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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