7-74338861-C-T

Position:

• chr7-74338861-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003388.5(CLIP2):​c.535C>T​(p.Pro179Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00413 in 1,608,964 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (47 hom.)
• Consequence: CLIP2 NM_003388.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.70

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058303773).
• BP6: Variant 7-74338861-C-T is Benign according to our data. Variant chr7-74338861-C-T is described in ClinVar as [Benign]. Clinvar id is 771871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 484 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLIP2	NM_003388.5	c.535C>T	p.Pro179Ser	missense_variant	3/17	ENST00000223398.11
CLIP2	NM_032421.3	c.535C>T	p.Pro179Ser	missense_variant	3/16
CLIP2	XM_047420800.1	c.535C>T	p.Pro179Ser	missense_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLIP2	ENST00000223398.11	c.535C>T	p.Pro179Ser	missense_variant	3/17	5	NM_003388.5	P3
CLIP2	ENST00000361545.9	c.535C>T	p.Pro179Ser	missense_variant	3/16	1		A1

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 483 AN: 152244 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000988

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00450

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00435 AC: 1053 AN: 241994 Hom.: 12 AF XY: 0.00491 AC XY: 651 AN XY: 132622

Gnomad AFR exome AF: 0.000854

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.00423

Gnomad EAS exome AF: 0.000388

Gnomad SAS exome AF: 0.0105

Gnomad FIN exome AF: 0.000222

Gnomad NFE exome AF: 0.00494

Gnomad OTH exome AF: 0.00399

GnomAD4 exome AF: 0.00423 AC: 6163 AN: 1456602 Hom.: 47 Cov.: 33 AF XY: 0.00458 AC XY: 3317 AN XY: 724888

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.00437

Gnomad4 EAS exome AF: 0.000454

Gnomad4 SAS exome AF: 0.0102

Gnomad4 FIN exome AF: 0.000352

Gnomad4 NFE exome AF: 0.00414

Gnomad4 OTH exome AF: 0.00495

GnomAD4 genome AF: 0.00318 AC: 484 AN: 152362 Hom.: 3 Cov.: 32 AF XY: 0.00313 AC XY: 233 AN XY: 74508

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00300

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00450

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00480 Hom.: 5

Bravo AF: 0.00317

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00230 AC: 10

ESP6500EA AF: 0.00363 AC: 31

ExAC AF: 0.00440 AC: 531

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00654

EpiControl AF: 0.00741

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	CLIP2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	.;T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.095
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;T;.
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.070	T;T;T
Sift4G	Uncertain	0.055	T;D;D
Polyphen		0.0070	B;B;B
Vest4		0.34
MVP		0.43
MPC		0.76
ClinPred		0.023	T
GERP RS		4.9
Varity_R		0.067
gMVP		0.60

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: rs61739991; hg19: chr7-73753191;