12-431936-A-G

Position:

• chr12-431936-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032358.4(CCDC77):​c.654A>G​(p.Ile218Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: CCDC77 NM_032358.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.201

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04928556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC77	NM_032358.4	c.654A>G	p.Ile218Met	missense_variant	8/13	ENST00000239830.9	NP_115734.1
CCDC77	NM_001130146.2	c.558A>G	p.Ile186Met	missense_variant	7/12		NP_001123618.1
CCDC77	NM_001130147.2	c.558A>G	p.Ile186Met	missense_variant	7/12		NP_001123619.1
CCDC77	NM_001130148.2	c.558A>G	p.Ile186Met	missense_variant	6/11		NP_001123620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC77	ENST00000239830.9	c.654A>G	p.Ile218Met	missense_variant	8/13	2	NM_032358.4	ENSP00000239830	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

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 09, 2022

The c.654A>G (p.I218M) 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 654, causing the isoleucine (I) at amino acid position 218 to be replaced by a methionine (M). 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	0.079
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.28
DANN	Benign	0.21
DEOGEN2	Benign	0.024	.;.;T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.64	.;T;T;T;.
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.049	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;.;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.030	N;N;N;N;N
REVEL	Benign	0.030
Sift	Benign	0.18	T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		0.013	.;.;.;B;.
Vest4		0.096
MutPred		0.16		.;.;.;Gain of catalytic residue at D217 (P = 0.0708);.;
MVP		0.27
MPC		0.12
ClinPred		0.066	T
GERP RS		-8.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.027
gMVP		0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-541102;