2-108786843-G-C

Position:

• chr2-108786843-G-C

Variant summary

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

The NM_144978.3(CCDC138):​c.21G>C​(p.Lys7Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,440,636 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: CCDC138 NM_144978.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

Genes affected

CCDC138 (HGNC:26531): (coiled-coil domain containing 138)

RANBP2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC138	NM_144978.3	c.21G>C	p.Lys7Asn	missense_variant	1/15	ENST00000295124.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC138	ENST00000295124.9	c.21G>C	p.Lys7Asn	missense_variant	1/15	2	NM_144978.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000933 AC: 2 AN: 214438 Hom.: 0 AF XY: 0.0000173 AC XY: 2 AN XY: 115520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000751

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1440636 Hom.: 0 Cov.: 31 AF XY: 0.00000840 AC XY: 6 AN XY: 714696

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: 0.0000726

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000832 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3474

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

May 14, 2024

The c.21G>C (p.K7N) alteration is located in exon 1 (coding exon 1) of the CCDC138 gene. This alteration results from a G to C substitution at nucleotide position 21, causing the lysine (K) at amino acid position 7 to be replaced by an asparagine (N). 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	Pathogenic	0.87
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.019	.;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Uncertain	0.034	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.68	N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.21	B;P
Vest4		0.56
MutPred		0.21		Loss of methylation at K7 (P = 0.0015);Loss of methylation at K7 (P = 0.0015);
MVP		0.87
MPC		0.21
ClinPred		0.92	D
GERP RS		2.5
Varity_R		0.45
gMVP		0.048

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs750585962; hg19: chr2-109403299;