11-14464983-G-A

Position:

• chr11-14464983-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001144061.2(COPB1):​c.2338C>T​(p.His780Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,992 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COPB1 NM_001144061.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42050594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COPB1	NM_001144061.2	c.2338C>T	p.His780Tyr	missense_variant	18/22	ENST00000439561.7	NP_001137533.1
COPB1	NM_001144062.2	c.2338C>T	p.His780Tyr	missense_variant	18/22		NP_001137534.1
COPB1	NM_016451.5	c.2338C>T	p.His780Tyr	missense_variant	18/22		NP_057535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COPB1	ENST00000439561.7	c.2338C>T	p.His780Tyr	missense_variant	18/22	1	NM_001144061.2	ENSP00000397873.2
COPB1	ENST00000249923.7	c.2338C>T	p.His780Tyr	missense_variant	18/22	1		ENSP00000249923.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460992 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726796

Gnomad4 AFR exome AF: 0.0000598

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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 10, 2022

The c.2338C>T (p.H780Y) alteration is located in exon 18 (coding exon 17) of the COPB1 gene. This alteration results from a C to T substitution at nucleotide position 2338, causing the histidine (H) at amino acid position 780 to be replaced by a tyrosine (Y). 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	Benign	0.14
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.24
Sift	Benign	0.099	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.049	B;B
Vest4		0.44
MutPred		0.74		Loss of disorder (P = 0.0644);Loss of disorder (P = 0.0644);
MVP		0.44
MPC		0.26
ClinPred		0.80	D
GERP RS		5.7
Varity_R		0.32
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs1850250080; hg19: chr11-14486529;