NM_024692.6:c.254T>G

Variant names:

• chr2-29131378-T-G
• NM_024692.6:c.254T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024692.6(CLIP4):​c.254T>G​(p.Ile85Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. I85T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLIP4 NM_024692.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024692.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIP4	NM_024692.6	MANE Select	c.254T>G	p.Ile85Ser	missense	Exon 3 of 16	NP_078968.3
	CLIP4	NM_001287527.2		c.254T>G	p.Ile85Ser	missense	Exon 3 of 16	NP_001274456.1	Q8N3C7-1
	CLIP4	NM_001287528.2		c.254T>G	p.Ile85Ser	missense	Exon 3 of 15	NP_001274457.1	Q8N3C7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIP4	ENST00000320081.10	TSL:1 MANE Select	c.254T>G	p.Ile85Ser	missense	Exon 3 of 16	ENSP00000327009.5	Q8N3C7-1
	CLIP4	ENST00000687506.1		c.254T>G	p.Ile85Ser	missense	Exon 3 of 16	ENSP00000509486.1	A0A8I5KTC6
	CLIP4	ENST00000404424.5	TSL:5	c.254T>G	p.Ile85Ser	missense	Exon 3 of 16	ENSP00000385594.1	Q8N3C7-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.88
MutPred		0.63		Loss of stability (P = 0.0189)
MVP		0.97
MPC		0.65
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.73
gMVP		0.89
Mutation Taster		=228/72	polymorphism

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

hg19: chr2-29354244;