7-74338897-G-A

Position:

• chr7-74338897-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003388.5(CLIP2):​c.571G>A​(p.Val191Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,604,762 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00083 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: CLIP2 NM_003388.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030345231).
• BS2: High AC in GnomAd4 at 127 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLIP2	NM_003388.5	c.571G>A	p.Val191Ile	missense_variant	3/17	ENST00000223398.11	NP_003379.4
CLIP2	NM_032421.3	c.571G>A	p.Val191Ile	missense_variant	3/16		NP_115797.2
CLIP2	XM_047420800.1	c.571G>A	p.Val191Ile	missense_variant	3/13		XP_047276756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLIP2	ENST00000223398.11	c.571G>A	p.Val191Ile	missense_variant	3/17	5	NM_003388.5	ENSP00000223398	P3
CLIP2	ENST00000361545.9	c.571G>A	p.Val191Ile	missense_variant	3/16	1		ENSP00000355151	A1

Frequencies

GnomAD3 genomes AF: 0.000834 AC: 127 AN: 152214 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000637 AC: 152 AN: 238774 Hom.: 0 AF XY: 0.000610 AC XY: 80 AN XY: 131056

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.000995

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.000833

GnomAD4 exome AF: 0.00108 AC: 1574 AN: 1452430 Hom.: 0 Cov.: 33 AF XY: 0.00105 AC XY: 759 AN XY: 722944

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000995

Gnomad4 NFE exome AF: 0.00133

Gnomad4 OTH exome AF: 0.000597

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152332 Hom.: 1 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74488

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00162

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00119 Hom.: 1

Bravo AF: 0.000733

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000469 AC: 2

ESP6500EA AF: 0.000951 AC: 8

ExAC AF: 0.000614 AC: 74

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.000948

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

Aug 12, 2021

The c.571G>A (p.V191I) alteration is located in exon 3 (coding exon 2) of the CLIP2 gene. This alteration results from a G to A substitution at nucleotide position 571, causing the valine (V) at amino acid position 191 to be replaced by an isoleucine (I). 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	0.085
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.080	.;T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.78	T;T;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.030	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.81	L;L;L
MutationTaster	Benign	0.77	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.45	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.96	D;P;P
Vest4		0.093
MVP		0.61
MPC		0.55
ClinPred		0.028	T
GERP RS		4.7
Varity_R		0.058
gMVP		0.19

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: rs75967845; hg19: chr7-73753227; COSMIC: COSV99034238;