12-428848-A-G

Position:

• chr12-428848-A-G

Variant summary

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

The NM_032358.4(CCDC77):​c.493A>G​(p.Lys165Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCDC77 NM_032358.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.53

Genes affected

CCDC77 (HGNC:28203): (coiled-coil domain containing 77) Located in centrosome. [provided by Alliance of Genome Resources, Apr 2022]

CCDC77 (HGNC:):

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=0.30243725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC77	NM_032358.4	c.493A>G	p.Lys165Glu	missense_variant	6/13	ENST00000239830.9	NP_115734.1
CCDC77	NM_001130146.2	c.397A>G	p.Lys133Glu	missense_variant	5/12		NP_001123618.1
CCDC77	NM_001130147.2	c.397A>G	p.Lys133Glu	missense_variant	5/12		NP_001123619.1
CCDC77	NM_001130148.2	c.397A>G	p.Lys133Glu	missense_variant	4/11		NP_001123620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC77	ENST00000239830.9	c.493A>G	p.Lys165Glu	missense_variant	6/13	2	NM_032358.4	ENSP00000239830.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456920 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725042

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: 0.00

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

Feb 06, 2023

The c.493A>G (p.K165E) alteration is located in exon 6 (coding exon 4) of the CCDC77 gene. This alteration results from a A to G substitution at nucleotide position 493, causing the lysine (K) at amino acid position 165 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	0.12
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	.;.;T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	.;T;T;T;.
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.30	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.9	.;.;.;M;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.97	.;.;.;D;.
Vest4		0.48
MutPred		0.41		.;.;.;Loss of methylation at K165 (P = 2e-04);.;
MVP		0.64
MPC		0.52
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.41
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-538014;