NM_024692.6:c.568G>C

Variant names:

• chr2-29135586-G-C
• rs779241531
• NM_024692.6:c.568G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024692.6(CLIP4):​c.568G>C​(p.Ala190Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,108 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLIP4 NM_024692.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.64

Genes affected

CLIP4 (HGNC:26108): (CAP-Gly domain containing linker protein family member 4) Predicted to enable microtubule plus-end binding activity. Predicted to be involved in cytoplasmic microtubule organization. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIP4	NM_024692.6	c.568G>C	p.Ala190Pro	missense_variant	Exon 6 of 16	ENST00000320081.10	NP_078968.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIP4	ENST00000320081.10	c.568G>C	p.Ala190Pro	missense_variant	Exon 6 of 16	1	NM_024692.6	ENSP00000327009.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458108 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725258

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.568G>C (p.A190P) alteration is located in exon 6 (coding exon 5) of the CLIP4 gene. This alteration results from a G to C substitution at nucleotide position 568, causing the alanine (A) at amino acid position 190 to be replaced by a proline (P). 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	Uncertain	0.35
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	.;.;T;T;.;.
Eigen	Benign	0.027
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;.;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.69	D;D;D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.34	N;.;N;N;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.8	D;D;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.22	T;T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T;T
Polyphen		0.28	.;.;B;B;.;.
Vest4		0.61
MutPred		0.72		Loss of catalytic residue at A190 (P = 0.0077);.;Loss of catalytic residue at A190 (P = 0.0077);Loss of catalytic residue at A190 (P = 0.0077);Loss of catalytic residue at A190 (P = 0.0077);.;
MVP		0.81
MPC		0.23
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.75
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: 16

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

Publications

LitVar

Other links and lift over

dbSNP: rs779241531; hg19: chr2-29358452;