15-68710836-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006091.5(CORO2B):c.438C>A(p.His146Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,638 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CORO2B NM_006091.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.565

Genes affected

CORO2B (HGNC:2256): (coronin 2B) Enables talin binding activity and vinculin binding activity. Acts upstream of or within several processes, including negative regulation of cell-substrate adhesion; regulation of actin cytoskeleton organization; and regulation of establishment of protein localization. Located in focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CORO2B	NM_006091.5	c.438C>A	p.His146Gln	missense_variant	4/12	ENST00000261861.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CORO2B	ENST00000261861.10	c.438C>A	p.His146Gln	missense_variant	4/12	1	NM_006091.5	P4
CORO2B	ENST00000540068.6	c.423C>A	p.His141Gln	missense_variant	4/12	5		A1
CORO2B	ENST00000543950.3	c.423C>A	p.His141Gln	missense_variant	4/12	2		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458638 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725214

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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

Dec 15, 2022

The c.438C>A (p.H146Q) alteration is located in exon 4 (coding exon 4) of the CORO2B gene. This alteration results from a C to A substitution at nucleotide position 438, causing the histidine (H) at amino acid position 146 to be replaced by a glutamine (Q). 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	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D;.;.;D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.5	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.8	D;D;D;D
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.95
MutPred		0.73		Loss of loop (P = 0.1242);.;.;.;
MVP		0.79
MPC		1.8
ClinPred		1.0	D
GERP RS		2.2
Varity_R		0.93
gMVP		0.66

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: chr15-69003175;