2-238848464-C-T

Variant names:

• chr2-238848464-C-T
• rs903088398
• NM_001271893.4:c.249C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_001271893.4(TWIST2):​c.249C>T​(p.Asn83Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,412,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TWIST2 NM_001271893.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.361
• Publications: 0 publications found

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]

TWIST2 Gene-Disease associations (from GenCC):

• ablepharon macrostomia syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Barber-Say syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• focal facial dermal dysplasia type III

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-238848464-C-T is Benign according to our data. Variant chr2-238848464-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 725730.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.361 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271893.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TWIST2	NM_001271893.4	MANE Select	c.249C>T	p.Asn83Asn	synonymous	Exon 1 of 2	NP_001258822.1	Q8WVJ9
	TWIST2	NM_057179.3		c.249C>T	p.Asn83Asn	synonymous	Exon 1 of 2	NP_476527.1	Q8WVJ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TWIST2	ENST00000612363.2	TSL:1 MANE Select	c.249C>T	p.Asn83Asn	synonymous	Exon 1 of 2	ENSP00000482581.1	Q8WVJ9
	TWIST2	ENST00000448943.2	TSL:1	c.249C>T	p.Asn83Asn	synonymous	Exon 1 of 2	ENSP00000405176.2	Q8WVJ9
	TWIST2	ENST00000710607.1		c.249C>T	p.Asn83Asn	synonymous	Exon 1 of 2	ENSP00000518373.1	Q8WVJ9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000283 AC: 4 AN: 1412472 Hom.: 0 Cov.: 31 AF XY: 0.00000429 AC XY: 3 AN XY: 698688

African (AFR) AF: 0.00 AC: 0 AN: 32194

American (AMR) AF: 0.00 AC: 0 AN: 37920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25398

East Asian (EAS) AF: 0.00 AC: 0 AN: 36970

South Asian (SAS) AF: 0.00 AC: 0 AN: 80306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000367 AC: 4 AN: 1090074

Other (OTH) AF: 0.00 AC: 0 AN: 58838

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	14
DANN	Benign	0.97
PhyloP100		0.36
PromoterAI		-0.028	Neutral
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs903088398; hg19: chr2-239757105;