chr9-98132193-A-G

Position:

• chr9-98132193-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_052820.4(CORO2A):​c.757T>C​(p.Trp253Arg) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CORO2A NM_052820.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

CORO2A (HGNC:2255): (coronin 2A) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This protein contains 5 WD repeats, and has a structural similarity with actin-binding proteins: the D. discoideum coronin and the human p57 protein, suggesting that this protein may also be an actin-binding protein that regulates cell motility. Alternative splicing of this gene generates 2 transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CORO2A	NM_052820.4	c.757T>C	p.Trp253Arg	missense_variant	6/12	ENST00000375077.5	NP_438171.1
CORO2A	NM_003389.3	c.757T>C	p.Trp253Arg	missense_variant	6/12		NP_003380.3
CORO2A	XM_011518986.4	c.757T>C	p.Trp253Arg	missense_variant	6/12		XP_011517288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CORO2A	ENST00000375077.5	c.757T>C	p.Trp253Arg	missense_variant	6/12	1	NM_052820.4	ENSP00000364218.4
CORO2A	ENST00000343933.9	c.757T>C	p.Trp253Arg	missense_variant	6/12	1		ENSP00000343746.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2024

The c.757T>C (p.W253R) alteration is located in exon 6 (coding exon 5) of the CORO2A gene. This alteration results from a T to C substitution at nucleotide position 757, causing the tryptophan (W) at amino acid position 253 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-13	D;D
REVEL	Uncertain	0.56
Sift	Benign	0.12	T;T
Sift4G	Benign	0.13	T;T
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.79		Gain of disorder (P = 0.0076);Gain of disorder (P = 0.0076);
MVP		0.52
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.85
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-100894475;