rs17362588

Positions:

• chr2-178856319-G-A
• chr2-178856319-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173648.4(CCDC141):​c.2803C>T​(p.Arg935Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0762 in 1,608,436 control chromosomes in the GnomAD database, including 5,410 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R935Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.060 (363 hom., cov: 32)
  • Exomes 𝑓: 0.078 (5047 hom.)
• Consequence: CCDC141 NM_173648.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.20

Genes affected

CCDC141 (HGNC:26821): (coiled-coil domain containing 141) Predicted to be involved in axon guidance and cell adhesion. Predicted to act upstream of or within centrosome localization and cerebral cortex radially oriented cell migration. Predicted to be located in centrosome; cytoplasm; and plasma membrane. Predicted to be active in neuron projection. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028259456).
• BP6: Variant 2-178856319-G-A is Benign according to our data. Variant chr2-178856319-G-A is described in ClinVar as [Benign]. Clinvar id is 1231630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC141	NM_173648.4	c.2803C>T	p.Arg935Trp	missense_variant	18/24	ENST00000443758.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC141	ENST00000443758.7	c.2803C>T	p.Arg935Trp	missense_variant	18/24	5	NM_173648.4	P1
	ENST00000652826.1	n.306+27665G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0603 AC: 9155 AN: 151946 Hom.: 363 Cov.: 32

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0656

Gnomad ASJ AF: 0.0554

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0268

Gnomad FIN AF: 0.0724

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0914

Gnomad OTH AF: 0.0628

GnomAD3 exomes AF: 0.0603 AC: 15016 AN: 248924 Hom.: 570 AF XY: 0.0607 AC XY: 8175 AN XY: 134598

Gnomad AFR exome AF: 0.0135

Gnomad AMR exome AF: 0.0490

Gnomad ASJ exome AF: 0.0522

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.0275

Gnomad FIN exome AF: 0.0725

Gnomad NFE exome AF: 0.0867

Gnomad OTH exome AF: 0.0725

GnomAD4 exome AF: 0.0779 AC: 113436 AN: 1456372 Hom.: 5047 Cov.: 30 AF XY: 0.0768 AC XY: 55638 AN XY: 724436

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.0508

Gnomad4 ASJ exome AF: 0.0518

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0292

Gnomad4 FIN exome AF: 0.0730

Gnomad4 NFE exome AF: 0.0887

Gnomad4 OTH exome AF: 0.0722

GnomAD4 genome AF: 0.0602 AC: 9152 AN: 152064 Hom.: 363 Cov.: 32 AF XY: 0.0596 AC XY: 4433 AN XY: 74336

Gnomad4 AFR AF: 0.0160

Gnomad4 AMR AF: 0.0655

Gnomad4 ASJ AF: 0.0554

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0270

Gnomad4 FIN AF: 0.0724

Gnomad4 NFE AF: 0.0915

Gnomad4 OTH AF: 0.0621

Alfa AF: 0.0818 Hom.: 1357

Bravo AF: 0.0560

TwinsUK AF: 0.0874 AC: 324

ALSPAC AF: 0.0760 AC: 293

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.0902 AC: 775

ExAC AF: 0.0617 AC: 7490

Asia WGS AF: 0.0110 AC: 38 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 29748316, 30012220) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Pathogenic	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.79	P;P
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
ClinPred		0.035	T
GERP RS		5.0

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

LitVar

Other links and lift over

dbSNP: rs17362588; hg19: chr2-179721046; COSMIC: COSV55371770;