Genetic Variant CCDC121:p.Ala136Ser (chr2-27627394-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024584.5(CCDC121):c.406G>T(p.Ala136Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A136V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CCDC121
NM_024584.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.184

Variant links:

Genes affected

CCDC121 (HGNC:25833): (coiled-coil domain containing 121)

CCDC121 links:

ENSG00000259080 (HGNC:):

ENSG00000259080 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06473085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC121	NM_024584.5 link	c.406G>T	p.Ala136Ser	missense_variant	Exon 2 of 2	ENST00000324364.4	NP_078860.2	Q6ZUS5-1
CCDC121	NM_001142683.3 link	c.892G>T	p.Ala298Ser	missense_variant	Exon 2 of 2		NP_001136155.1	Q6ZUS5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCDC121	ENST00000324364.4 link	c.406G>T	p.Ala136Ser	missense_variant	Exon 2 of 2	1	NM_024584.5	ENSP00000339087.2	Q6ZUS5-1
CCDC121	ENST00000394775.3 link	c.892G>T	p.Ala298Ser	missense_variant	Exon 2 of 2	1		ENSP00000412150.2	Q6ZUS5-2
ENSG00000259080	ENST00000505973.1 link	n.1389-2465C>A		intron_variant	Intron 12 of 17	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.892G>T (p.A298S) alteration is located in exon 2 (coding exon 2) of the CCDC121 gene. This alteration results from a G to T substitution at nucleotide position 892, causing the alanine (A) at amino acid position 298 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

2.7

DANN

Benign

0.60

DEOGEN2

Benign

0.017

T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.42

T;T

M_CAP

Benign

0.0061

MetaRNN

Benign

0.065

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.58

N;N

REVEL

Benign

0.038

Sift

Benign

0.36

T;T

Sift4G

Benign

0.38

T;T

Polyphen

0.56

P;.

Vest4

0.091

MutPred

0.17

Gain of relative solvent accessibility (P = 0.0023);.;

MVP

0.16

MPC

0.20

ClinPred

0.35

GERP RS

1.6

Varity_R

0.051

gMVP

0.017

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over