12-122274172-TAA-TAAA

Variant names:

• chr12-122274172-T-TA
• rs376224001
• NM_001247997.2:c.3967-11dupT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001247997.2(CLIP1):​c.3967-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,404,870 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (0 hom.)
• Consequence: CLIP1 NM_001247997.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.14
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Variant has high frequency in the AFR (0.0104) population. However there is too low homozygotes in high coverage region: (expected more than 3, got 1).
• BP6: Variant 12-122274172-T-TA is Benign according to our data. Variant chr12-122274172-T-TA is described in ClinVar as Benign. ClinVar VariationId is 1336261.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3967-11dupT		intron	N/A	NP_001234926.1	P30622-3
	CLIP1	NM_001389291.1		c.6097-11dupT		intron	N/A	NP_001376220.1
	CLIP1	NM_002956.3		c.3934-11dupT		intron	N/A	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.3967-11dupT		intron	N/A	ENSP00000479322.1	P30622-3
	CLIP1	ENST00000358808.6	TSL:1	c.3934-11dupT		intron	N/A	ENSP00000351665.2	P30622-1
	CLIP1	ENST00000537178.5	TSL:1	c.3829-11dupT		intron	N/A	ENSP00000445531.1	P30622-2

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 442 AN: 149608 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00887

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00194

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00330

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.0000999

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000327

Gnomad OTH AF: 0.00245

GnomAD2 exomes AF: 0.00302 AC: 468 AN: 155128 AF XY: 0.00257

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.00375

Gnomad ASJ exome AF: 0.00128

Gnomad EAS exome AF: 0.00581

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.00275

GnomAD4 exome AF: 0.00337 AC: 4231 AN: 1255164 Hom.: 0 Cov.: 24 AF XY: 0.00320 AC XY: 1999 AN XY: 624512

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

African (AFR) AF: 0.0114 AC: 324 AN: 28434

American (AMR) AF: 0.00323 AC: 120 AN: 37194

Ashkenazi Jewish (ASJ) AF: 0.00276 AC: 60 AN: 21732

East Asian (EAS) AF: 0.00315 AC: 105 AN: 33300

South Asian (SAS) AF: 0.00170 AC: 123 AN: 72296

European-Finnish (FIN) AF: 0.00245 AC: 112 AN: 45692

Middle Eastern (MID) AF: 0.00236 AC: 12 AN: 5084

European-Non Finnish (NFE) AF: 0.00333 AC: 3199 AN: 960030

Other (OTH) AF: 0.00342 AC: 176 AN: 51402

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00297 AC: 444 AN: 149706 Hom.: 1 Cov.: 32 AF XY: 0.00322 AC XY: 235 AN XY: 73064

African (AFR) AF: 0.00889 AC: 364 AN: 40932

American (AMR) AF: 0.00194 AC: 29 AN: 14980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00331 AC: 17 AN: 5136

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4754

European-Finnish (FIN) AF: 0.0000999 AC: 1 AN: 10014

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000327 AC: 22 AN: 67196

Other (OTH) AF: 0.00243 AC: 5 AN: 2060

Alfa AF: 0.00854 Hom.: 0

Bravo AF: 0.00315

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-4.1
BranchPoint Hunter		4.0
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: rs376224001; hg19: chr12-122758719; COSMIC: COSV56809668; COSMIC: COSV56809668;