NM_001271893.4:c.192G>A

Variant names:

• chr2-238848407-G-A
• rs761752428
• NM_001271893.4:c.192G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS1

The NM_001271893.4(TWIST2):​c.192G>A​(p.Leu64Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000455 in 1,537,632 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: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: TWIST2 NM_001271893.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.37
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-238848407-G-A is Benign according to our data. Variant chr2-238848407-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 797374.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000217 (33/152316) while in subpopulation AFR AF = 0.000745 (31/41588). AF 95% confidence interval is 0.000539. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.192G>A	p.Leu64Leu	synonymous	Exon 1 of 2	NP_001258822.1	Q8WVJ9
	TWIST2	NM_057179.3		c.192G>A	p.Leu64Leu	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.192G>A	p.Leu64Leu	synonymous	Exon 1 of 2	ENSP00000482581.1	Q8WVJ9
	TWIST2	ENST00000448943.2	TSL:1	c.192G>A	p.Leu64Leu	synonymous	Exon 1 of 2	ENSP00000405176.2	Q8WVJ9
	TWIST2	ENST00000710607.1		c.192G>A	p.Leu64Leu	synonymous	Exon 1 of 2	ENSP00000518373.1	Q8WVJ9

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000626 AC: 9 AN: 143680 AF XY: 0.0000523

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 37 AN: 1385316 Hom.: 0 Cov.: 31 AF XY: 0.0000176 AC XY: 12 AN XY: 683576

African (AFR) AF: 0.00101 AC: 32 AN: 31582

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35726

South Asian (SAS) AF: 0.00 AC: 0 AN: 79196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078892

Other (OTH) AF: 0.0000863 AC: 5 AN: 57952

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74474

African (AFR) AF: 0.000745 AC: 31 AN: 41588

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000227

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	13
DANN	Uncertain	0.98
PhyloP100		2.4
PromoterAI		-0.019	Neutral
Mutation Taster		=94/6	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: rs761752428; hg19: chr2-239757048;