rs387906974

Positions:

• chr2-238848408-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001271893.4(TWIST2):​c.193C>T​(p.Gln65Ter) variant causes a stop gained 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 (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TWIST2 NM_001271893.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.54

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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-238848408-C-T is Pathogenic according to our data. Variant chr2-238848408-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30679.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TWIST2	NM_001271893.4	c.193C>T	p.Gln65Ter	stop_gained	1/2	ENST00000612363.2	NP_001258822.1
TWIST2	NM_057179.3	c.193C>T	p.Gln65Ter	stop_gained	1/2		NP_476527.1
TWIST2	XR_007069137.1	n.324C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TWIST2	ENST00000612363.2	c.193C>T	p.Gln65Ter	stop_gained	1/2	1	NM_001271893.4	ENSP00000482581	P1
TWIST2	ENST00000448943.2	c.193C>T	p.Gln65Ter	stop_gained	1/2	1		ENSP00000405176	P1
TWIST2	ENST00000710607.1	c.193C>T	p.Gln65Ter	stop_gained	1/2			ENSP00000518373	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1385516 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 683690

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Focal facial dermal dysplasia type III Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 13, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A
Vest4		0.81
GERP RS		4.8

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: rs387906974; hg19: chr2-239757049;