8-27765231-T-A

Variant names:

• chr8-27765231-T-A
• rs762598226
• NM_018246.3:c.49A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018246.3(CCDC25):​c.49A>T​(p.Ile17Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000741 in 1,350,110 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I17V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CCDC25 NM_018246.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.69
• Publications: 0 publications found

Genes affected

CCDC25 (HGNC:25591): (coiled-coil domain containing 25) Enables DNA binding activity. Involved in positive regulation of cell motility. Located in endomembrane system. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC25	NM_018246.3	c.49A>T	p.Ile17Phe	missense_variant	Exon 2 of 9	ENST00000356537.9	NP_060716.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC25	ENST00000356537.9	c.49A>T	p.Ile17Phe	missense_variant	Exon 2 of 9	1	NM_018246.3	ENSP00000348933.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.41e-7 AC: 1 AN: 1350110 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 666334

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30372

American (AMR) AF: 0.00 AC: 0 AN: 34796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23814

East Asian (EAS) AF: 0.00 AC: 0 AN: 36444

South Asian (SAS) AF: 0.00 AC: 0 AN: 77918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5358

European-Non Finnish (NFE) AF: 9.62e-7 AC: 1 AN: 1039124

Other (OTH) AF: 0.00 AC: 0 AN: 55284

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.8	H;.
PhyloP100		1.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0030	D;.
Polyphen		0.90	P;.
Vest4		0.84
MutPred		0.61		Loss of stability (P = 0.0994);Loss of stability (P = 0.0994);
MVP		0.45
MPC		1.6
ClinPred		0.99	D
GERP RS		2.3
Varity_R		0.51
gMVP		0.89
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs762598226; hg19: chr8-27622748;