Genetic Variant CCDC137:p.Gln14His (chr17-81666808-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_199287.3(CCDC137):c.42G>T(p.Gln14His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000785 in 1,273,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

CCDC137
NM_199287.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.709

Publications

0 publications found

Variant links:

Genes affected

CCDC137 (HGNC:33451): (coiled-coil domain containing 137) Enables RNA binding activity. Located in chromosome and fibrillar center. [provided by Alliance of Genome Resources, Apr 2022]

CCDC137 links:

OXLD1 (HGNC:27901): (oxidoreductase like domain containing 1)

OXLD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17578098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC137	NM_199287.3 link	c.42G>T	p.Gln14His	missense_variant	Exon 1 of 6	ENST00000329214.13	NP_954981.1	Q6PK04
OXLD1	NM_001039842.3 link	c.-231C>A		upstream_gene_variant		ENST00000374741.4	NP_001034931.1	Q5BKU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC137	ENST00000329214.13 link	c.42G>T	p.Gln14His	missense_variant	Exon 1 of 6	1	NM_199287.3	ENSP00000329360.8		Q6PK04
OXLD1	ENST00000374741.4 link	c.-231C>A		upstream_gene_variant		1	NM_001039842.3	ENSP00000363873.3		Q5BKU9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.85e-7

AC:

AN:

1273774

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

624970

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

25792

American (AMR)

AF:

0.00

AC:

AN:

19928

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18736

East Asian (EAS)

AF:

0.00

AC:

AN:

30660

South Asian (SAS)

AF:

0.00

AC:

AN:

61242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4168

European-Non Finnish (NFE)

AF:

9.78e-7

AC:

AN:

1022166

Other (OTH)

AF:

0.00

AC:

AN:

51540

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 18, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.42G>T (p.Q14H) alteration is located in exon 1 (coding exon 1) of the CCDC137 gene. This alteration results from a G to T substitution at nucleotide position 42, causing the glutamine (Q) at amino acid position 14 to be replaced by a histidine (H). 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

0.16

BayesDel_addAF

Benign

-0.044

BayesDel_noAF

Benign

-0.30

CADD

Benign

7.2

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.0033

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.41

.;T

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.69

N;.

PhyloP100

-0.71

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.73

N;.

REVEL

Uncertain

0.35

Sift

Benign

0.16

T;.

Sift4G

Benign

0.14

T;T

Polyphen

0.77

P;.

Vest4

0.13

MutPred

0.17

Gain of methylation at R12 (P = 0.053);Gain of methylation at R12 (P = 0.053);

MVP

0.64

MPC

0.057

ClinPred

0.49

GERP RS

-2.4

PromoterAI

-0.0094

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.043

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over