chr2-238848283-A-C

Variant names:

• chr2-238848283-A-C
• rs2106345702
• NM_001271893.4:c.68A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001271893.4(TWIST2):​c.68A>C​(p.Glu23Ala) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TWIST2 NM_001271893.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.88

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

Our verdict: Uncertain_significance. The variant received 3 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
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2588135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWIST2	NM_001271893.4	c.68A>C	p.Glu23Ala	missense_variant	Exon 1 of 2	ENST00000612363.2	NP_001258822.1
TWIST2	NM_057179.3	c.68A>C	p.Glu23Ala	missense_variant	Exon 1 of 2		NP_476527.1
TWIST2	XR_007069137.1	n.199A>C		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TWIST2	ENST00000612363.2	c.68A>C	p.Glu23Ala	missense_variant	Exon 1 of 2	1	NM_001271893.4	ENSP00000482581.1
TWIST2	ENST00000448943.2	c.68A>C	p.Glu23Ala	missense_variant	Exon 1 of 2	1		ENSP00000405176.2
TWIST2	ENST00000710607.1	c.68A>C	p.Glu23Ala	missense_variant	Exon 1 of 2			ENSP00000518373.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with TWIST2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces glutamic acid with alanine at codon 23 of the TWIST2 protein (p.Glu23Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-0.018
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	1.3	L;L
PhyloP100		8.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	N;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.021	D;.
Sift4G	Benign	0.23	T;T
Polyphen		0.012	B;B
Vest4		0.17
MutPred		0.20		Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);
MVP		0.98
MPC		1.8
ClinPred		0.82	D
GERP RS		4.7
PromoterAI		-0.033	Neutral
Varity_R		0.19
gMVP		0.48
Mutation Taster		=60/40	polymorphism

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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Other links and lift over

dbSNP: rs2106345702; hg19: chr2-239756924;