2-178856319-G-A

Variant names:

• chr2-178856319-G-A
• rs17362588
• NM_173648.4:c.2803C>T

Variant summary

Our verdict is Benign. The variant received -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. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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:3
• Conservation: PhyloP100: 2.20
• Publications: 50 publications found

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]

CCDC141 Gene-Disease associations (from GenCC):

• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000287149 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173648.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC141	NM_173648.4	MANE Select	c.2803C>T	p.Arg935Trp	missense	Exon 18 of 24	NP_775919.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC141	ENST00000443758.7	TSL:5 MANE Select	c.2803C>T	p.Arg935Trp	missense	Exon 18 of 24	ENSP00000390190.2
	CCDC141	ENST00000343876.6	TSL:1	c.1135C>T	p.Arg379Trp	missense	Exon 8 of 13	ENSP00000344627.2
	ENSG00000287149	ENST00000652826.1		n.306+27665G>A		intron	N/A

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

GnomAD2 exomes AF: 0.0603 AC: 15016 AN: 248924 AF XY: 0.0607

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 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

African (AFR) AF: 0.0122 AC: 408 AN: 33332

American (AMR) AF: 0.0508 AC: 2229 AN: 43904

Ashkenazi Jewish (ASJ) AF: 0.0518 AC: 1345 AN: 25966

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39596

South Asian (SAS) AF: 0.0292 AC: 2491 AN: 85438

European-Finnish (FIN) AF: 0.0730 AC: 3886 AN: 53224

Middle Eastern (MID) AF: 0.0665 AC: 381 AN: 5732

European-Non Finnish (NFE) AF: 0.0887 AC: 98349 AN: 1109020

Other (OTH) AF: 0.0722 AC: 4342 AN: 60160

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

African (AFR) AF: 0.0160 AC: 665 AN: 41466

American (AMR) AF: 0.0655 AC: 1001 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0554 AC: 192 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0270 AC: 130 AN: 4812

European-Finnish (FIN) AF: 0.0724 AC: 765 AN: 10572

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0915 AC: 6218 AN: 67976

Other (OTH) AF: 0.0621 AC: 131 AN: 2108

Alfa AF: 0.0792 Hom.: 2523

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29748316, 30012220)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
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
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.92	T
PhyloP100		2.2
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
ClinPred		0.035	T
GERP RS		5.0
Mutation Taster		=93/7	polymorphism (auto)

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