12-431917-A-G

Position:

• chr12-431917-A-G

Variant summary

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

The NM_032358.4(CCDC77):​c.635A>G​(p.Glu212Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000027 (0 hom.)
• Consequence: CCDC77 NM_032358.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30

Genes affected

CCDC77 (HGNC:28203): (coiled-coil domain containing 77) Located in centrosome. [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=0.093066484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC77	NM_032358.4	c.635A>G	p.Glu212Gly	missense_variant	8/13	ENST00000239830.9	NP_115734.1
CCDC77	NM_001130146.2	c.539A>G	p.Glu180Gly	missense_variant	7/12		NP_001123618.1
CCDC77	NM_001130147.2	c.539A>G	p.Glu180Gly	missense_variant	7/12		NP_001123619.1
CCDC77	NM_001130148.2	c.539A>G	p.Glu180Gly	missense_variant	6/11		NP_001123620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC77	ENST00000239830.9	c.635A>G	p.Glu212Gly	missense_variant	8/13	2	NM_032358.4	ENSP00000239830	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460458 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726676

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: 0.0000464

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

Jul 19, 2023

The c.635A>G (p.E212G) alteration is located in exon 8 (coding exon 6) of the CCDC77 gene. This alteration results from a A to G substitution at nucleotide position 635, causing the glutamic acid (E) at amino acid position 212 to be replaced by a glycine (G). 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	0.065
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.028	.;.;T;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.79
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.50	.;T;T;T;.
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.093	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;.;.;L;.
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D
REVEL	Benign	0.11
Sift	Benign	0.20	T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		0.0030	.;.;.;B;.
Vest4		0.11
MutPred		0.18		.;.;.;Gain of catalytic residue at D217 (P = 0.0157);.;
MVP		0.46
MPC		0.14
ClinPred		0.12	T
GERP RS		2.0
Varity_R		0.069
gMVP		0.25

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: rs953914325; hg19: chr12-541083;