12-122316798-C-T

Variant names:

• chr12-122316798-C-T
• rs887990606
• NM_001247997.2:c.3424G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001247997.2(CLIP1):​c.3424G>A​(p.Glu1142Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,443,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLIP1 NM_001247997.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.43

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19920364).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIP1	NM_001247997.2	c.3424G>A	p.Glu1142Lys	missense_variant	Exon 19 of 26	ENST00000620786.5	NP_001234926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIP1	ENST00000620786.5	c.3424G>A	p.Glu1142Lys	missense_variant	Exon 19 of 26	5	NM_001247997.2	ENSP00000479322.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1443216 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 716858

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3391G>A (p.E1131K) alteration is located in exon 18 (coding exon 17) of the CLIP1 gene. This alteration results from a G to A substitution at nucleotide position 3391, causing the glutamic acid (E) at amino acid position 1131 to be replaced by a lysine (K). 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	0.15
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	.;.;.;.;T;.;.;T
Eigen	Benign	0.083
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;.;D;D;D;D;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;.;.;.;L;.;.;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.1	.;N;N;N;.;N;.;N
REVEL	Benign	0.14
Sift	Benign	0.14	.;T;T;T;.;T;.;T
Sift4G	Uncertain	0.050	T;.;D;D;D;D;.;D
Polyphen		0.28, 0.18, 0.62	.;.;B;B;B;P;.;B
Vest4		0.79
MutPred		0.26		.;.;.;.;Gain of MoRF binding (P = 0.0084);.;.;Gain of MoRF binding (P = 0.0084);
MVP		0.81
MPC		0.48
ClinPred		0.82	D
GERP RS		6.0
Varity_R		0.16
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs887990606; hg19: chr12-122801345;