11-14466351-G-T

Variant names:

• chr11-14466351-G-T
• NM_001144061.2:c.2221C>A

Variant summary

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

The NM_001144061.2(COPB1):​c.2221C>A​(p.Leu741Met) variant causes a missense change involving the alteration of a non-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: COPB1 NM_001144061.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21

Genes affected

COPB1 (HGNC:2231): (COPI coat complex subunit beta 1) This gene encodes a protein subunit of the coatomer complex associated with non-clathrin coated vesicles. The coatomer complex, also known as the coat protein complex 1, forms in the cytoplasm and is recruited to the Golgi by activated guanosine triphosphatases. Once at the Golgi membrane, the coatomer complex may assist in the movement of protein and lipid components back to the endoplasmic reticulum. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2009]

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, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COPB1	NM_001144061.2	c.2221C>A	p.Leu741Met	missense_variant	Exon 17 of 22	ENST00000439561.7	NP_001137533.1
COPB1	NM_001144062.2	c.2221C>A	p.Leu741Met	missense_variant	Exon 17 of 22		NP_001137534.1
COPB1	NM_016451.5	c.2221C>A	p.Leu741Met	missense_variant	Exon 17 of 22		NP_057535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COPB1	ENST00000439561.7	c.2221C>A	p.Leu741Met	missense_variant	Exon 17 of 22	1	NM_001144061.2	ENSP00000397873.2
COPB1	ENST00000249923.7	c.2221C>A	p.Leu741Met	missense_variant	Exon 17 of 22	1		ENSP00000249923.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2221C>A (p.L741M) alteration is located in exon 17 (coding exon 16) of the COPB1 gene. This alteration results from a C to A substitution at nucleotide position 2221, causing the leucine (L) at amino acid position 741 to be replaced by a methionine (M). 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	0.57
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.0087	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.027	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.85		Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);
MVP		0.68
MPC		0.81
ClinPred		0.93	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.56

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: chr11-14487897; COSMIC: COSV99999239;