2-108798582-A-G

Position:

• chr2-108798582-A-G

Variant summary

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

The NM_144978.3(CCDC138):​c.731A>G​(p.Lys244Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K244E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CCDC138 NM_144978.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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.731A>G	p.Lys244Arg	missense_variant	6/15	ENST00000295124.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC138	ENST00000295124.9	c.731A>G	p.Lys244Arg	missense_variant	6/15	2	NM_144978.3	P1
CCDC138	ENST00000412964.6	c.731A>G	p.Lys244Arg	missense_variant	6/14	1
CCDC138	ENST00000456512.1	c.425A>G	p.Lys142Arg	missense_variant	3/9	5
CCDC138	ENST00000409529.6	c.*536A>G		3_prime_UTR_variant, NMD_transcript_variant	6/14	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

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

Feb 05, 2024

The c.731A>G (p.K244R) alteration is located in exon 6 (coding exon 6) of the CCDC138 gene. This alteration results from a A to G substitution at nucleotide position 731, causing the lysine (K) at amino acid position 244 to be replaced by an arginine (R). 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	0.11
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.13	T;T
Sift4G	Uncertain	0.030	D;T
Polyphen		0.97	D;D
Vest4		0.51
MutPred		0.23		Loss of ubiquitination at K244 (P = 0.0127);Loss of ubiquitination at K244 (P = 0.0127);
MVP		0.94
MPC		0.14
ClinPred		0.94	D
GERP RS		5.7
Varity_R		0.18
gMVP		0.048

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr2-109415038;