2-29143781-G-A

Variant names:

• chr2-29143781-G-A
• rs201519559
• NM_024692.6:c.721G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024692.6(CLIP4):​c.721G>A​(p.Ala241Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,374 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: CLIP4 NM_024692.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 3 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 2 ACMG points.

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

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.721G>A	p.Ala241Thr	missense	Exon 7 of 16	NP_078968.3
	CLIP4	NM_001287527.2		c.721G>A	p.Ala241Thr	missense	Exon 7 of 16	NP_001274456.1	Q8N3C7-1
	CLIP4	NM_001287528.2		c.721G>A	p.Ala241Thr	missense	Exon 7 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.721G>A	p.Ala241Thr	missense	Exon 7 of 16	ENSP00000327009.5	Q8N3C7-1
	CLIP4	ENST00000687506.1		c.721G>A	p.Ala241Thr	missense	Exon 7 of 16	ENSP00000509486.1	A0A8I5KTC6
	CLIP4	ENST00000404424.5	TSL:5	c.721G>A	p.Ala241Thr	missense	Exon 7 of 16	ENSP00000385594.1	Q8N3C7-1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000918 AC: 23 AN: 250458 AF XY: 0.0000812

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1461064 Hom.: 0 Cov.: 32 AF XY: 0.0000578 AC XY: 42 AN XY: 726866

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.000112 AC: 5 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39690

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86250

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1111462

Other (OTH) AF: 0.0000331 AC: 2 AN: 60332

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74468

African (AFR) AF: 0.0000241 AC: 1 AN: 41566

American (AMR) AF: 0.000131 AC: 2 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000148 AC: 18

ClinVar

ClinVar submissions as Germline

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	0.79
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		10
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.59
MVP		0.90
MPC		0.53
ClinPred		0.56	D
GERP RS		5.5
Varity_R		0.18
gMVP		0.63
Mutation Taster		=49/51	disease causing

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

dbSNP: rs201519559; hg19: chr2-29366647; COSMIC: COSV100191781;