5-151199020-C-T

Position:

• chr5-151199020-C-T

Variant summary

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

The NM_015621.3(CCDC69):​c.296G>A​(p.Gly99Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CCDC69 NM_015621.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.207

Genes affected

CCDC69 (HGNC:24487): (coiled-coil domain containing 69) Predicted to enable microtubule binding activity. Involved in spindle midzone assembly. Located in spindle midzone. [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=0.04563105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC69	NM_015621.3	c.296G>A	p.Gly99Glu	missense_variant	4/9	ENST00000355417.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC69	ENST00000355417.7	c.296G>A	p.Gly99Glu	missense_variant	4/9	1	NM_015621.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

Gnomad4 AFR exome AF: 0.0000597

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Nov 21, 2023

The c.296G>A (p.G99E) alteration is located in exon 4 (coding exon 4) of the CCDC69 gene. This alteration results from a G to A substitution at nucleotide position 296, causing the glycine (G) at amino acid position 99 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	0.095
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.5
DANN	Benign	0.24
DEOGEN2	Benign	0.00059	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.94	N
REVEL	Benign	0.049
Sift	Benign	0.63	T
Sift4G	Benign	1.0	T
Polyphen		0.074	B
Vest4		0.18
MutPred		0.17		Gain of solvent accessibility (P = 0.0596);
MVP		0.076
MPC		0.038
ClinPred		0.13	T
GERP RS		3.1
Varity_R		0.078
gMVP		0.093

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: rs1752741754; hg19: chr5-150578581; COSMIC: COSV104669492;