17-81667760-A-G

Variant names:

• chr17-81667760-A-G
• rs368297027
• NM_199287.3:c.166A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_199287.3(CCDC137):​c.166A>G​(p.Lys56Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,692 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: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CCDC137 NM_199287.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.603
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.204025).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC137	NM_199287.3	c.166A>G	p.Lys56Glu	missense_variant	Exon 2 of 6	ENST00000329214.13	NP_954981.1
CCDC137	XM_047435910.1	c.-45A>G		5_prime_UTR_variant	Exon 2 of 6		XP_047291866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC137	ENST00000329214.13	c.166A>G	p.Lys56Glu	missense_variant	Exon 2 of 6	1	NM_199287.3	ENSP00000329360.8

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152152 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000802 AC: 2 AN: 249262 AF XY: 0.00000739

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461540 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727052

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152152 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000666 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.166A>G (p.K56E) alteration is located in exon 2 (coding exon 2) of the CCDC137 gene. This alteration results from a A to G substitution at nucleotide position 166, causing the lysine (K) at amino acid position 56 to be replaced by a glutamic acid (E). 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	0.00083	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.52	.;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.8	M;.
PhyloP100		0.60
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Benign	0.24
Sift	Uncertain	0.016	D;.
Sift4G	Uncertain	0.024	D;D
Polyphen		0.30	B;.
Vest4		0.18
MVP		0.82
MPC		0.12
ClinPred		0.31	T
GERP RS		0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.57
Mutation Taster		=92/8	polymorphism

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: rs368297027; hg19: chr17-79634790;