2-238848336-G-C

Variant names:

• chr2-238848336-G-C
• rs1692170055
• NM_001271893.4:c.121G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001271893.4(TWIST2):​c.121G>C​(p.Glu41Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,154 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: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TWIST2 NM_001271893.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.51

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24015015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWIST2	NM_001271893.4	c.121G>C	p.Glu41Gln	missense_variant	Exon 1 of 2	ENST00000612363.2	NP_001258822.1
TWIST2	NM_057179.3	c.121G>C	p.Glu41Gln	missense_variant	Exon 1 of 2		NP_476527.1
TWIST2	XR_007069137.1	n.252G>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.121G>C	p.Glu41Gln	missense_variant	Exon 1 of 2	1	NM_001271893.4	ENSP00000482581.1
TWIST2	ENST00000448943.2	c.121G>C	p.Glu41Gln	missense_variant	Exon 1 of 2	1		ENSP00000405176.2
TWIST2	ENST00000710607.1	c.121G>C	p.Glu41Gln	missense_variant	Exon 1 of 2			ENSP00000518373.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	.;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	2.0	M;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.75	N;.
REVEL	Uncertain	0.45
Sift	Benign	0.057	T;.
Sift4G	Benign	0.39	T;T
Polyphen		0.065	B;B
Vest4		0.16
MutPred		0.21		Gain of MoRF binding (P = 0.0719);Gain of MoRF binding (P = 0.0719);
MVP		0.99
MPC		2.6
ClinPred		0.86	D
GERP RS		4.9
Varity_R		0.20
gMVP		0.61

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: rs1692170055; hg19: chr2-239756977;