7-74338738-A-C

Position:

• chr7-74338738-A-C

Variant summary

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

The NM_003388.5(CLIP2):​c.412A>C​(p.Ile138Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,006 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: CLIP2 NM_003388.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27

Genes affected

CLIP2 (HGNC:2586): (CAP-Gly domain containing linker protein 2) The protein encoded by this gene belongs to the family of cytoplasmic linker proteins, which have been proposed to mediate the interaction between specific membranous organelles and microtubules. This protein was found to associate with both microtubules and an organelle called the dendritic lamellar body. This gene is hemizygously deleted in Williams syndrome, a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. Alternative splicing of this gene generates 2 transcript variants. [provided by RefSeq, Jul 2008]

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/exons	MANE	UniProt
CLIP2	NM_003388.5	c.412A>C	p.Ile138Leu	missense_variant	3/17	ENST00000223398.11
CLIP2	NM_032421.3	c.412A>C	p.Ile138Leu	missense_variant	3/16
CLIP2	XM_047420800.1	c.412A>C	p.Ile138Leu	missense_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLIP2	ENST00000223398.11	c.412A>C	p.Ile138Leu	missense_variant	3/17	5	NM_003388.5	P3
CLIP2	ENST00000361545.9	c.412A>C	p.Ile138Leu	missense_variant	3/16	1		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446006 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 718696

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Dec 08, 2023

The c.412A>C (p.I138L) alteration is located in exon 3 (coding exon 2) of the CLIP2 gene. This alteration results from a A to C substitution at nucleotide position 412, causing the isoleucine (I) at amino acid position 138 to be replaced by a leucine (L). 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	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;.
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.085	N;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.7	N;N;N
REVEL	Pathogenic	0.73
Sift	Benign	0.097	T;T;T
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.68
MutPred		0.58		Gain of disorder (P = 0.0667);Gain of disorder (P = 0.0667);Gain of disorder (P = 0.0667);
MVP		0.81
MPC		0.92
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.35
gMVP		0.76

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: rs1277195906; hg19: chr7-73753068;