3-112638040-T-G

Variant summary

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

The NM_199511.3(CCDC80):c.1866A>C(p.Lys622Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,324 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CCDC80 NM_199511.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.139

Genes affected

CCDC80 (HGNC:30649): (coiled-coil domain containing 80) Predicted to enable glycosaminoglycan binding activity. Predicted to act upstream of or within extracellular matrix organization; positive regulation of cell-substrate adhesion; and response to bacterium. Predicted to be located in extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC80	NM_199511.3	c.1866A>C	p.Lys622Asn	missense_variant	2/8	ENST00000206423.8
CCDC80	NM_199512.3	c.1866A>C	p.Lys622Asn	missense_variant	2/8
CCDC80	XM_047447495.1	c.1899A>C	p.Lys633Asn	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC80	ENST00000206423.8	c.1866A>C	p.Lys622Asn	missense_variant	2/8	1	NM_199511.3	P1
CCDC80	ENST00000439685.6	c.1866A>C	p.Lys622Asn	missense_variant	2/8	1		P1
CCDC80	ENST00000461431.1	c.60A>C	p.Lys20Asn	missense_variant	1/6	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449324 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 720626

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Aug 08, 2022

The c.1866A>C (p.K622N) alteration is located in exon 2 (coding exon 1) of the CCDC80 gene. This alteration results from a A to C substitution at nucleotide position 1866, causing the lysine (K) at amino acid position 622 to be replaced by an asparagine (N). 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	0.63
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.036	T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.97	D;D
Vest4		0.74
MutPred		0.45		Loss of methylation at K622 (P = 0.0067);Loss of methylation at K622 (P = 0.0067);
MVP		0.74
MPC		0.74
ClinPred		0.97	D
GERP RS		-0.66
Varity_R		0.35
gMVP		0.46

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: rs1936242040; hg19: chr3-112356887;