7-74338850-C-T

Position:

• chr7-74338850-C-T

Variant summary

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

The NM_003388.5(CLIP2):​c.524C>T​(p.Thr175Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,457,364 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CLIP2 NM_003388.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.29

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=0.35511935).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLIP2	NM_003388.5	c.524C>T	p.Thr175Met	missense_variant	3/17	ENST00000223398.11	NP_003379.4
CLIP2	NM_032421.3	c.524C>T	p.Thr175Met	missense_variant	3/16		NP_115797.2
CLIP2	XM_047420800.1	c.524C>T	p.Thr175Met	missense_variant	3/13		XP_047276756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLIP2	ENST00000223398.11	c.524C>T	p.Thr175Met	missense_variant	3/17	5	NM_003388.5	ENSP00000223398	P3
CLIP2	ENST00000361545.9	c.524C>T	p.Thr175Met	missense_variant	3/16	1		ENSP00000355151	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1457364 Hom.: 0 Cov.: 33 AF XY: 0.00000552 AC XY: 4 AN XY: 725242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

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

May 31, 2024

The c.524C>T (p.T175M) alteration is located in exon 3 (coding exon 2) of the CLIP2 gene. This alteration results from a C to T substitution at nucleotide position 524, causing the threonine (T) at amino acid position 175 to be replaced by a methionine (M). 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	0.10
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;T;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T;T;.
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.81	L;L;L
MutationTaster	Benign	0.85	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.46
MutPred		0.14		Loss of glycosylation at T175 (P = 0.0185);Loss of glycosylation at T175 (P = 0.0185);Loss of glycosylation at T175 (P = 0.0185);
MVP		0.64
MPC		1.4
ClinPred		0.78	D
GERP RS		3.9
Varity_R		0.064
gMVP		0.26

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: rs868936675; hg19: chr7-73753180; COSMIC: COSV56280172;