12-122316808-G-A

Variant names:

• chr12-122316808-G-A
• rs532538060
• NM_001247997.2:c.3414C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001247997.2(CLIP1):​c.3414C>T​(p.Asn1138Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000691 in 1,590,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CLIP1 NM_001247997.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.587
• Publications: 0 publications found

Genes affected

CLIP1 (HGNC:10461): (CAP-Gly domain containing linker protein 1) The protein encoded by this gene links endocytic vesicles to microtubules. This gene is highly expressed in Reed-Sternberg cells of Hodgkin disease. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

CLIP1 Gene-Disease associations (from GenCC):

• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP7: Synonymous conserved (PhyloP=0.587 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001247997.2. 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
	CLIP1	NM_001247997.2	MANE Select	c.3414C>T	p.Asn1138Asn	synonymous	Exon 19 of 26	NP_001234926.1	P30622-3
	CLIP1	NM_001389291.1		c.5544C>T	p.Asn1848Asn	synonymous	Exon 18 of 25	NP_001376220.1
	CLIP1	NM_002956.3		c.3381C>T	p.Asn1127Asn	synonymous	Exon 18 of 25	NP_002947.1	P30622-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIP1	ENST00000620786.5	TSL:5 MANE Select	c.3414C>T	p.Asn1138Asn	synonymous	Exon 19 of 26	ENSP00000479322.1	P30622-3
	CLIP1	ENST00000358808.6	TSL:1	c.3381C>T	p.Asn1127Asn	synonymous	Exon 18 of 25	ENSP00000351665.2	P30622-1
	CLIP1	ENST00000537178.5	TSL:1	c.3276C>T	p.Asn1092Asn	synonymous	Exon 17 of 24	ENSP00000445531.1	P30622-2

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151262 Hom.: 0 Cov.: 31

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: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000857 AC: 2 AN: 233478 AF XY: 0.0000159

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000695 AC: 10 AN: 1439514 Hom.: 0 Cov.: 28 AF XY: 0.00000979 AC XY: 7 AN XY: 714920

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32640

American (AMR) AF: 0.00 AC: 0 AN: 41216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25588

East Asian (EAS) AF: 0.00 AC: 0 AN: 38932

South Asian (SAS) AF: 0.0000878 AC: 7 AN: 79698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1103178

Other (OTH) AF: 0.00 AC: 0 AN: 59450

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000100371), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151380 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73944

African (AFR) AF: 0.00 AC: 0 AN: 41236

American (AMR) AF: 0.00 AC: 0 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67854

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.9
DANN	Benign	0.66
PhyloP100		0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs532538060; hg19: chr12-122801355;