7-74338805-C-G

Variant names:

• chr7-74338805-C-G
• rs543387438
• NM_003388.5:c.479C>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_003388.5(CLIP2):​c.479C>G​(p.Ser160Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000714 in 1,611,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: CLIP2 NM_003388.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.27

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3149535).
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIP2	NM_003388.5	c.479C>G	p.Ser160Cys	missense_variant	Exon 3 of 17	ENST00000223398.11	NP_003379.4
CLIP2	NM_032421.3	c.479C>G	p.Ser160Cys	missense_variant	Exon 3 of 16		NP_115797.2
CLIP2	XM_047420800.1	c.479C>G	p.Ser160Cys	missense_variant	Exon 3 of 13		XP_047276756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIP2	ENST00000223398.11	c.479C>G	p.Ser160Cys	missense_variant	Exon 3 of 17	5	NM_003388.5	ENSP00000223398.6
CLIP2	ENST00000361545.9	c.479C>G	p.Ser160Cys	missense_variant	Exon 3 of 16	1		ENSP00000355151.5

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000407 AC: 10 AN: 245710 Hom.: 0 AF XY: 0.0000448 AC XY: 6 AN XY: 133950

Gnomad AFR exome AF: 0.0000639

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000541

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000699 AC: 102 AN: 1458972 Hom.: 0 Cov.: 33 AF XY: 0.0000675 AC XY: 49 AN XY: 725922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

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: 0.0000818

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74482

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.0000604

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.479C>G (p.S160C) alteration is located in exon 3 (coding exon 2) of the CLIP2 gene. This alteration results from a C to G substitution at nucleotide position 479, causing the serine (S) at amino acid position 160 to be replaced by a cysteine (C). 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	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	.;T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D;D;.
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.97	L;L;L
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.015	D;D;D
Sift4G	Uncertain	0.053	T;D;D
Polyphen		1.0	D;D;D
Vest4		0.46
MutPred		0.26		Loss of phosphorylation at S160 (P = 0.0395);Loss of phosphorylation at S160 (P = 0.0395);Loss of phosphorylation at S160 (P = 0.0395);
MVP		0.73
MPC		1.6
ClinPred		0.20	T
GERP RS		3.7
Varity_R		0.17
gMVP		0.73

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: rs543387438; hg19: chr7-73753135;