chr2-238848438-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001271893.4(TWIST2):c.223G>A(p.Glu75Lys) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E75A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TWIST2
NM_001271893.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.52

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

ablepharon macrostomia syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
Barber-Say syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
focal facial dermal dysplasia type III
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

TWIST2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-238848439-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 208076.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.1324 (below the threshold of 3.09). Trascript score misZ: 0.22546 (below the threshold of 3.09). GenCC associations: The gene is linked to ablepharon macrostomia syndrome, focal facial dermal dysplasia type III, Barber-Say syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 2-238848438-G-A is Pathogenic according to our data. Variant chr2-238848438-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TWIST2	NM_001271893.4 link	c.223G>A	p.Glu75Lys	missense_variant	Exon 1 of 2	ENST00000612363.2	NP_001258822.1
TWIST2	NM_057179.3 link	c.223G>A	p.Glu75Lys	missense_variant	Exon 1 of 2		NP_476527.1
TWIST2	XR_007069137.1 link	n.354G>A		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TWIST2	ENST00000612363.2 link	c.223G>A	p.Glu75Lys	missense_variant	Exon 1 of 2	1	NM_001271893.4	ENSP00000482581.1
TWIST2	ENST00000448943.2 link	c.223G>A	p.Glu75Lys	missense_variant	Exon 1 of 2	1		ENSP00000405176.2
TWIST2	ENST00000710607.1 link	c.223G>A	p.Glu75Lys	missense_variant	Exon 1 of 2			ENSP00000518373.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.17e-7

AC:

AN:

1395318

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689052

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31744

American (AMR)

AF:

0.00

AC:

AN:

36218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25214

East Asian (EAS)

AF:

0.00

AC:

AN:

36068

South Asian (SAS)

AF:

0.00

AC:

AN:

79508

European-Finnish (FIN)

AF:

0.0000250

AC:

AN:

39940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082610

Other (OTH)

AF:

0.00

AC:

AN:

58308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ablepharon macrostomia syndrome

Pathogenic:3

Jun 07, 2020

Department of Pediatrics, Prince of Songkla University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous missense p.Glu75Lys was reported to be associated with Ablepharon macrostomia syndrome in 7 families (Marchegiani et al. 2015). This variant was not found in ExAC database and our in-house Thai exome database (consisted of 1084 Thai exome controls). We classified this as pathogenic variant by ACMG Guidelines, 2015 based on >/=2 strong criteria [PS1, PS2, and PS3 (Functional study by Marchegiani et al. 2015)].

Sep 11, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v4: 1 heterozygote(s), 0 homozygote(s)) ; This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in individuals with ablepharon macrostomia syndrome (AMS), including multiple de novo occurrences (PMID: 26119818), and has been classified as pathogenic by clinical laboratories (ClinVar); Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. The p.(Glu75Gln) and p.(Glu75Ala) variants have been reported in individuals with Barber-Say syndrome (BSS), including de novo occurrences (PMID: 26119818), and have been classified as pathogenic by clinical laboratories (ClinVar); Variant is located in a hotspot region or cluster of PATHOGENIC variants. Multiple recurrent missense variants associated with AMS or BSS have been reported at this amino acid residue (PMID: 26119818); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change; Strong phenotype match for this individual; This variant has been shown to be de novo in the proband by trio analysis (parental status confirmed). Additional information: Variant is predicted to result in a missense amino acid change from Glu to Lys; This variant is heterozygous; This gene is associated with both recessive and dominant disease. Monoallelic variants in this gene have been reported in individuals with ablepharon-macrostomia syndrome (MIM#200110), and Barber-Say syndrome (MIM#209885). Biallelic variants have been reported in individuals with Setleis syndrome (MIM#227260); Dominant negative and loss of function are reported mechanisms of disease in this gene. Heterozygous variants in TWIST2 are reported to have a dominant-negative effect in individuals with AMS and BSS (PMID: 28369379), whereas biallelic loss of function variants are reported to cause Setleis syndrome (PMID: 20691403).

Jul 02, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Inborn genetic diseases

Pathogenic:1

Oct 09, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;D

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.0

.;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.4

M;M

PhyloP100

9.5

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-4.0

D;.

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.95

ClinPred

1.0

GERP RS

4.8

PromoterAI

0.085

Neutral

(source)

Varity_R

0.84

gMVP

1.0

Mutation Taster

=11/89

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over