2-238848438-G-GAGCGCC

Position:

• chr2-238848438-G-GAGCGCC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_001271893.4(TWIST2):​c.229_234dup​(p.Gln77_Arg78dup) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TWIST2 NM_001271893.4 inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.88

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain bHLH (size 51) in uniprot entity TWST2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001271893.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001271893.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 2-238848438-G-GAGCGCC is Pathogenic according to our data. Variant chr2-238848438-G-GAGCGCC is described in ClinVar as [Pathogenic]. Clinvar id is 208079.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TWIST2	NM_001271893.4	c.229_234dup	p.Gln77_Arg78dup	inframe_insertion	1/2	ENST00000612363.2
TWIST2	NM_057179.3	c.229_234dup	p.Gln77_Arg78dup	inframe_insertion	1/2
TWIST2	XR_007069137.1	n.360_365dup		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TWIST2	ENST00000612363.2	c.229_234dup	p.Gln77_Arg78dup	inframe_insertion	1/2	1	NM_001271893.4	P1
TWIST2	ENST00000448943.2	c.229_234dup	p.Gln77_Arg78dup	inframe_insertion	1/2	1		P1
TWIST2	ENST00000710607.1	c.229_234dup	p.Gln77_Arg78dup	inframe_insertion	1/2			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Barber-Say syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 02, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869320750; hg19: chr2-239757079;