17-81672537-G-T

Variant names:

• chr17-81672537-G-T
• rs1376814763
• NM_199287.3:c.703G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_199287.3(CCDC137):​c.703G>T​(p.Gly235Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000353 in 1,416,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G235V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CCDC137 NM_199287.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.587
• 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08462712).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC137	NM_199287.3	c.703G>T	p.Gly235Cys	missense_variant	Exon 6 of 6	ENST00000329214.13	NP_954981.1
CCDC137	XM_047435910.1	c.493G>T	p.Gly165Cys	missense_variant	Exon 6 of 6		XP_047291866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC137	ENST00000329214.13	c.703G>T	p.Gly235Cys	missense_variant	Exon 6 of 6	1	NM_199287.3	ENSP00000329360.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000353 AC: 5 AN: 1416242 Hom.: 0 Cov.: 31 AF XY: 0.00000571 AC XY: 4 AN XY: 700478

African (AFR) AF: 0.00 AC: 0 AN: 32448

American (AMR) AF: 0.00 AC: 0 AN: 37836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25348

East Asian (EAS) AF: 0.00 AC: 0 AN: 37136

South Asian (SAS) AF: 0.00 AC: 0 AN: 80710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000367 AC: 4 AN: 1088736

Other (OTH) AF: 0.0000170 AC: 1 AN: 58690

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.079	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.52	.;T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.085	T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.6	M;.
PhyloP100		0.59
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.6	D;.
REVEL	Benign	0.26
Sift	Uncertain	0.010	D;.
Sift4G	Uncertain	0.043	D;D
Polyphen		0.013	B;.
Vest4		0.32
MutPred		0.29		Gain of catalytic residue at P234 (P = 0.0634);.;
MVP		0.31
MPC		0.37
ClinPred		0.39	T
GERP RS		-0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.20
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1376814763; hg19: chr17-79639567; COSMIC: COSV105201209; COSMIC: COSV105201209;