chr2-238848228-T-G

Variant names:

• chr2-238848228-T-G
• rs1314192968
• NM_001271893.4:c.13T>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001271893.4(TWIST2):​c.13T>G​(p.Ser5Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000774 in 1,292,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: TWIST2 NM_001271893.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.76

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28237763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWIST2	NM_001271893.4	c.13T>G	p.Ser5Ala	missense_variant	Exon 1 of 2	ENST00000612363.2	NP_001258822.1
TWIST2	NM_057179.3	c.13T>G	p.Ser5Ala	missense_variant	Exon 1 of 2		NP_476527.1
TWIST2	XR_007069137.1	n.144T>G		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.13T>G	p.Ser5Ala	missense_variant	Exon 1 of 2	1	NM_001271893.4	ENSP00000482581.1
TWIST2	ENST00000448943.2	c.13T>G	p.Ser5Ala	missense_variant	Exon 1 of 2	1		ENSP00000405176.2
TWIST2	ENST00000710607.1	c.13T>G	p.Ser5Ala	missense_variant	Exon 1 of 2			ENSP00000518373.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.74e-7 AC: 1 AN: 1292088 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 628472

Gnomad4 AFR exome AF: 0.00

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: 9.73e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.0082
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.66	.;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.1	N;.
REVEL	Uncertain	0.42
Sift	Benign	0.068	T;.
Sift4G	Benign	0.27	T;T
Polyphen		0.0010	B;B
Vest4		0.40
MutPred		0.15		Loss of phosphorylation at P5 (P = 0.0013);Loss of phosphorylation at P5 (P = 0.0013);
MVP		0.96
MPC		1.4
ClinPred		0.57	D
GERP RS		3.5
Varity_R		0.12
gMVP		0.57

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: rs1314192968; hg19: chr2-239756869;