7-51027780-C-T

Variant names:

• chr7-51027780-C-T
• rs1260514822
• NM_015198.5:c.3316G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015198.5(COBL):​c.3316G>A​(p.Asp1106Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1106H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COBL NM_015198.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.52
• Publications: 0 publications found

Genes affected

COBL (HGNC:22199): (cordon-bleu WH2 repeat protein) This gene encodes a protein that contains WH2 domains (WASP, Wiskott-Aldrich syndrome protein, homology domain-2) that interact with actin. The encoded actin regulator protein is required for growth and assembly of brush border microvilli that play a role in maintaining intestinal homeostasis. A similar protein in mouse functions in midbrain neural tube closure. A pseudogene of this gene is located on chromosome X. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015198.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COBL	NM_015198.5	MANE Select	c.3316G>A	p.Asp1106Asn	missense	Exon 10 of 13	NP_056013.2
	COBL	NM_001410881.1		c.3562G>A	p.Asp1188Asn	missense	Exon 12 of 15	NP_001397810.1	O75128-2
	COBL	NM_001287436.3		c.3487G>A	p.Asp1163Asn	missense	Exon 11 of 14	NP_001274365.1	O75128-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COBL	ENST00000265136.12	TSL:1 MANE Select	c.3316G>A	p.Asp1106Asn	missense	Exon 10 of 13	ENSP00000265136.7	O75128-1
	COBL	ENST00000431948.6	TSL:1	c.3562G>A	p.Asp1188Asn	missense	Exon 12 of 15	ENSP00000413498.2	O75128-2
	COBL	ENST00000395542.6	TSL:1	c.3487G>A	p.Asp1163Asn	missense	Exon 11 of 14	ENSP00000378912.3	O75128-7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.54
MutPred		0.49		Gain of helix (P = 0.0022)
MVP		0.61
MPC		0.36
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.23
gMVP		0.22
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs1260514822; hg19: chr7-51095477;