Genetic Variant NM_173648.4:c.4369G>A (chr2-178834397-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_173648.4(CCDC141):c.4369G>A(p.Val1457Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00647 in 1,536,374 control chromosomes in the GnomAD database, including 48 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0067 ( 44 hom. )

Consequence

CCDC141
NM_173648.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.33

Variant links:

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 links:

ENSG00000287149 (HGNC:):

ENSG00000287149 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6

Variant 2-178834397-C-T is Benign according to our data. Variant chr2-178834397-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 773847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC141	NM_173648.4 link	c.4369G>A	p.Val1457Ile	missense_variant	Exon 24 of 24	ENST00000443758.7	NP_775919.3	Q6ZP82-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC141	ENST00000443758.7 link	c.4369G>A	p.Val1457Ile	missense_variant	Exon 24 of 24	5	NM_173648.4	ENSP00000390190.2		Q6ZP82-2

Frequencies

GnomAD3 genomes

AF:

0.00485

AC:

737

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00321

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00806

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00446

AC:

619

AN:

138646

Hom.:

AF XY:

0.00410

AC XY:

307

AN XY:

74884

show subpopulations

Gnomad AFR exome

AF:

0.00132

Gnomad AMR exome

AF:

0.00228

Gnomad ASJ exome

AF:

0.00960

Gnomad EAS exome

AF:

0.0000951

Gnomad SAS exome

AF:

0.000311

Gnomad FIN exome

AF:

0.00367

Gnomad NFE exome

AF:

0.00763

Gnomad OTH exome

AF:

0.00537

GnomAD4 exome

AF:

0.00665

AC:

9210

AN:

1384146

Hom.:

Cov.:

AF XY:

0.00662

AC XY:

4518

AN XY:

682986

show subpopulations

Gnomad4 AFR exome

AF:

0.00101

Gnomad4 AMR exome

AF:

0.00235

Gnomad4 ASJ exome

AF:

0.0101

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.000682

Gnomad4 FIN exome

AF:

0.00399

Gnomad4 NFE exome

AF:

0.00772

Gnomad4 OTH exome

AF:

0.00506

GnomAD4 genome

AF:

0.00484

AC:

737

AN:

152228

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

325

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00321

Gnomad4 NFE

AF:

0.00806

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00780

Hom.:

Bravo

AF:

0.00462

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00623

AC:

ExAC

AF:

0.00291

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CCDC141: BP4, BS2; ENSG00000287149: BS2 -

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypogonadotropic hypogonadism 7 with or without anosmia

Benign:1

Aug 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.79

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.66

M_CAP

Benign

0.031

MetaRNN

Benign

0.0073

MetaSVM

Benign

-0.83

PrimateAI

Benign

0.32

ClinPred

0.047

GERP RS

5.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.21

Position offset: -41

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over