2-164695372-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365672.2(COBLL1):c.2020A>G(p.Lys674Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COBLL1 NM_001365672.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.995

Genes affected

COBLL1 (HGNC:23571): (cordon-bleu WH2 repeat protein like 1) Enables cadherin binding activity. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17740306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COBLL1	NM_001365672.2	c.2020A>G	p.Lys674Glu	missense_variant	12/14	ENST00000652658.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COBLL1	ENST00000652658.2	c.2020A>G	p.Lys674Glu	missense_variant	12/14		NM_001365672.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251188 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461748 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727172

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: 0.00000180

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

Jun 05, 2023

The c.2134A>G (p.K712E) alteration is located in exon 12 (coding exon 12) of the COBLL1 gene. This alteration results from a A to G substitution at nucleotide position 2134, causing the lysine (K) at amino acid position 712 to be replaced by a glutamic acid (E). 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	0.094
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.024	T;.;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;.;.
MutationTaster	Benign	0.96	N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N;N;N;.
REVEL	Benign	0.18
Sift	Benign	0.11	T;T;T;.
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.073	B;.;.;.
Vest4		0.32
MutPred		0.28		Loss of methylation at K750 (P = 0.0045);.;.;.;
MVP		0.47
MPC		0.084
ClinPred		0.11	T
GERP RS		4.9
Varity_R		0.099
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1298904878; hg19: chr2-165551882;