2-108798501-A-G

Position:

• chr2-108798501-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144978.3(CCDC138):​c.650A>G​(p.Gln217Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,710 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: 6.8e-7 (0 hom.)
• Consequence: CCDC138 NM_144978.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.11

Genes affected

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

RANBP2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21609533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC138	NM_144978.3	c.650A>G	p.Gln217Arg	missense_variant	6/15	ENST00000295124.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC138	ENST00000295124.9	c.650A>G	p.Gln217Arg	missense_variant	6/15	2	NM_144978.3	P1
CCDC138	ENST00000412964.6	c.650A>G	p.Gln217Arg	missense_variant	6/14	1
CCDC138	ENST00000456512.1	c.344A>G	p.Gln115Arg	missense_variant	3/9	5
CCDC138	ENST00000409529.6	c.*455A>G		3_prime_UTR_variant, NMD_transcript_variant	6/14	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461710 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

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: 0.00

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

Jan 26, 2023

The c.650A>G (p.Q217R) 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 650, causing the glutamine (Q) at amino acid position 217 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	Benign	-0.0030	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.24
Sift	Benign	0.20	T;T
Sift4G	Uncertain	0.027	D;T
Polyphen		0.62	P;P
Vest4		0.32
MutPred		0.18		Gain of MoRF binding (P = 0.0173);Gain of MoRF binding (P = 0.0173);
MVP		0.89
MPC		0.076
ClinPred		0.80	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.054

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: chr2-109414957;