chr7-74338508-C-G

Variant names:

• chr7-74338508-C-G
• rs781989461
• NM_003388.5:c.182C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003388.5(CLIP2):​c.182C>G​(p.Pro61Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000584 in 1,610,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P61S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: CLIP2 NM_003388.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1270422).
• BS2: High AC in GnomAd4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003388.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIP2	NM_003388.5	MANE Select	c.182C>G	p.Pro61Arg	missense	Exon 3 of 17	NP_003379.4
	CLIP2	NM_032421.3		c.182C>G	p.Pro61Arg	missense	Exon 3 of 16	NP_115797.2	Q9UDT6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIP2	ENST00000223398.11	TSL:5 MANE Select	c.182C>G	p.Pro61Arg	missense	Exon 3 of 17	ENSP00000223398.6	Q9UDT6-1
	CLIP2	ENST00000361545.9	TSL:1	c.182C>G	p.Pro61Arg	missense	Exon 3 of 16	ENSP00000355151.5	Q9UDT6-2
	CLIP2	ENST00000884300.1		c.182C>G	p.Pro61Arg	missense	Exon 3 of 18	ENSP00000554359.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000289 AC: 7 AN: 242490 AF XY: 0.0000303

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000643

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000583 AC: 85 AN: 1458712 Hom.: 0 Cov.: 33 AF XY: 0.0000579 AC XY: 42 AN XY: 725566

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 85954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.0000765 AC: 85 AN: 1111150

Other (OTH) AF: 0.00 AC: 0 AN: 60278

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000902 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.11
Sift	Benign	0.042	D
Sift4G	Uncertain	0.021	D
Polyphen		0.14	B
Vest4		0.14
MVP		0.42
MPC		0.81
ClinPred		0.14	T
GERP RS		4.8
Varity_R		0.072
gMVP		0.42
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs781989461; hg19: chr7-73752838;