17-81670323-G-A

Variant names:

• chr17-81670323-G-A
• rs199850384
• NM_199287.3:c.367G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_199287.3(CCDC137):​c.367G>A​(p.Gly123Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,613,964 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: CCDC137 NM_199287.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.33
• Publications: 5 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010958016).
• BP6: Variant 17-81670323-G-A is Benign according to our data. Variant chr17-81670323-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2357685.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC137	NM_199287.3	c.367G>A	p.Gly123Arg	missense_variant	Exon 3 of 6	ENST00000329214.13	NP_954981.1
CCDC137	XM_047435910.1	c.157G>A	p.Gly53Arg	missense_variant	Exon 3 of 6		XP_047291866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC137	ENST00000329214.13	c.367G>A	p.Gly123Arg	missense_variant	Exon 3 of 6	1	NM_199287.3	ENSP00000329360.8

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000165 AC: 41 AN: 248816 AF XY: 0.000163

Gnomad AFR exome AF: 0.000908

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: 0.000222

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000105 AC: 154 AN: 1461648 Hom.: 1 Cov.: 39 AF XY: 0.000111 AC XY: 81 AN XY: 727100

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1111972

Other (OTH) AF: 0.000149 AC: 9 AN: 60392

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74472

African (AFR) AF: 0.000722 AC: 30 AN: 41572

American (AMR) AF: 0.000131 AC: 2 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000291 Hom.: 0

Bravo AF: 0.000351

ESP6500AA AF: 0.00180 AC: 7

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.000215 AC: 26

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 21, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.016
DANN	Benign	0.53
DEOGEN2	Benign	0.0013	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.68	.;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.23	N;.
PhyloP100		-2.3
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.30	N;.
REVEL	Benign	0.034
Sift	Benign	0.68	T;.
Sift4G	Benign	0.80	T;T
Polyphen		0.011	B;.
Vest4		0.090
MutPred		0.17		Gain of MoRF binding (P = 0.0234);.;
MVP		0.030
MPC		0.073
ClinPred		0.015	T
GERP RS		-7.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.028
gMVP		0.16
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199850384; hg19: chr17-79637353; COSMIC: COSV61303215; COSMIC: COSV61303215;