2-238848438-G-C

Position:

• chr2-238848438-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001271893.4(TWIST2):​c.223G>C​(p.Glu75Gln) 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. 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)
• Consequence: TWIST2 NM_001271893.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.52

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-238848438-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 2-238848438-G-C is Pathogenic according to our data. Variant chr2-238848438-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 208078.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TWIST2	NM_001271893.4	c.223G>C	p.Glu75Gln	missense_variant	1/2	ENST00000612363.2
TWIST2	NM_057179.3	c.223G>C	p.Glu75Gln	missense_variant	1/2
TWIST2	XR_007069137.1	n.354G>C		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TWIST2	ENST00000612363.2	c.223G>C	p.Glu75Gln	missense_variant	1/2	1	NM_001271893.4	P1
TWIST2	ENST00000448943.2	c.223G>C	p.Glu75Gln	missense_variant	1/2	1		P1
TWIST2	ENST00000710607.1	c.223G>C	p.Glu75Gln	missense_variant	1/2			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Barber-Say syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 06, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. The c.223G>C (p.E75Q) variant in the TWIST2 gene is the recurrent pathogenic variant causing Barber-Say syndrome [PMID 26119818, 27092433, 28680619]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.1	H;H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.0	D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.83		Gain of MoRF binding (P = 0.0542);Gain of MoRF binding (P = 0.0542);
MVP		0.96
MPC		2.9
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.87
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

LitVar

Other links and lift over

dbSNP: rs1553565140; hg19: chr2-239757079;