2-238848229-C-A

Variant names:

• chr2-238848229-C-A
• NM_001271893.4:c.14C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001271893.4(TWIST2):​c.14C>A​(p.Ser5Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 5.78

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWIST2	NM_001271893.4	c.14C>A	p.Ser5Tyr	missense_variant	Exon 1 of 2	ENST00000612363.2	NP_001258822.1
TWIST2	NM_057179.3	c.14C>A	p.Ser5Tyr	missense_variant	Exon 1 of 2		NP_476527.1
TWIST2	XR_007069137.1	n.145C>A		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.14C>A	p.Ser5Tyr	missense_variant	Exon 1 of 2	1	NM_001271893.4	ENSP00000482581.1
TWIST2	ENST00000448943.2	c.14C>A	p.Ser5Tyr	missense_variant	Exon 1 of 2	1		ENSP00000405176.2
TWIST2	ENST00000710607.1	c.14C>A	p.Ser5Tyr	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

Inborn genetic diseases Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14C>A (p.S5Y) alteration is located in exon 1 (coding exon 1) of the TWIST2 gene. This alteration results from a C to A substitution at nucleotide position 14, causing the serine (S) at amino acid position 5 to be replaced by a tyrosine (Y). 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	Benign	0.12
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.2	N;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.014	D;D
Polyphen		0.94	P;P
Vest4		0.47
MutPred		0.24		Gain of catalytic residue at S5 (P = 0.0744);Gain of catalytic residue at S5 (P = 0.0744);
MVP		0.99
MPC		2.8
ClinPred		0.91	D
GERP RS		4.7
Varity_R		0.28
gMVP		0.73

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.

Other links and lift over

hg19: chr2-239756870;