chr2-29121444-G-A

Position:

• chr2-29121444-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024692.6(CLIP4):​c.56G>A​(p.Arg19Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CLIP4 NM_024692.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15841803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLIP4	NM_024692.6	c.56G>A	p.Arg19Lys	missense_variant	2/16	ENST00000320081.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLIP4	ENST00000320081.10	c.56G>A	p.Arg19Lys	missense_variant	2/16	1	NM_024692.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461500 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727052

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.56G>A (p.R19K) alteration is located in exon 2 (coding exon 1) of the CLIP4 gene. This alteration results from a G to A substitution at nucleotide position 56, causing the arginine (R) at amino acid position 19 to be replaced by a lysine (K). 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	0.082
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.036	.;T;T;.
Eigen	Benign	-0.022
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.61	T;.;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.0	M;M;M;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.52	N;N;N;N
REVEL	Benign	0.068
Sift	Benign	0.43	T;T;T;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.17
MutPred		0.33		Gain of ubiquitination at R19 (P = 0.0121);Gain of ubiquitination at R19 (P = 0.0121);Gain of ubiquitination at R19 (P = 0.0121);Gain of ubiquitination at R19 (P = 0.0121);
MVP		0.72
MPC		0.11
ClinPred		0.48	T
GERP RS		5.2
Varity_R		0.12
gMVP		0.41

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: rs1215691854; hg19: chr2-29344310;