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GeneBe

2-182934830-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_013436.5(NCKAP1):c.2781C>G(p.Val927=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 1,424,956 control chromosomes in the GnomAD database, including 430,417 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 37680 hom., cov: 32)
Exomes 𝑓: 0.78 ( 392737 hom. )

Consequence

NCKAP1
NM_013436.5 splice_region, synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.341
Variant links:
Genes affected
NCKAP1 (HGNC:7666): (NCK associated protein 1) Contributes to small GTPase binding activity. Involved in Rac protein signal transduction; positive regulation of Arp2/3 complex-mediated actin nucleation; and positive regulation of lamellipodium assembly. Located in extracellular exosome and focal adhesion. Part of SCAR complex. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.47).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-182934830-G-C is Benign according to our data. Variant chr2-182934830-G-C is described in ClinVar as [Benign]. Clinvar id is 1268390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.341 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NCKAP1NM_013436.5 linkuse as main transcriptc.2781C>G p.Val927= splice_region_variant, synonymous_variant 26/31 ENST00000361354.9
NCKAP1NM_205842.3 linkuse as main transcriptc.2799C>G p.Val933= splice_region_variant, synonymous_variant 27/32
NCKAP1XM_006712200.4 linkuse as main transcriptc.2793C>G p.Val931= splice_region_variant, synonymous_variant 27/32
NCKAP1XM_006712201.4 linkuse as main transcriptc.2775C>G p.Val925= splice_region_variant, synonymous_variant 26/31

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NCKAP1ENST00000361354.9 linkuse as main transcriptc.2781C>G p.Val927= splice_region_variant, synonymous_variant 26/311 NM_013436.5 P4Q9Y2A7-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.673
AC:
102225
AN:
151942
Hom.:
37667
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.349
Gnomad AMI
AF:
0.857
Gnomad AMR
AF:
0.756
Gnomad ASJ
AF:
0.702
Gnomad EAS
AF:
0.960
Gnomad SAS
AF:
0.872
Gnomad FIN
AF:
0.870
Gnomad MID
AF:
0.677
Gnomad NFE
AF:
0.780
Gnomad OTH
AF:
0.681
GnomAD3 exomes
AF:
0.782
AC:
171399
AN:
219312
Hom.:
68830
AF XY:
0.789
AC XY:
93611
AN XY:
118632
show subpopulations
Gnomad AFR exome
AF:
0.330
Gnomad AMR exome
AF:
0.809
Gnomad ASJ exome
AF:
0.701
Gnomad EAS exome
AF:
0.955
Gnomad SAS exome
AF:
0.862
Gnomad FIN exome
AF:
0.865
Gnomad NFE exome
AF:
0.775
Gnomad OTH exome
AF:
0.782
GnomAD4 exome
AF:
0.780
AC:
992663
AN:
1272896
Hom.:
392737
Cov.:
20
AF XY:
0.783
AC XY:
500696
AN XY:
639436
show subpopulations
Gnomad4 AFR exome
AF:
0.313
Gnomad4 AMR exome
AF:
0.802
Gnomad4 ASJ exome
AF:
0.701
Gnomad4 EAS exome
AF:
0.957
Gnomad4 SAS exome
AF:
0.862
Gnomad4 FIN exome
AF:
0.865
Gnomad4 NFE exome
AF:
0.779
Gnomad4 OTH exome
AF:
0.767
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.673
AC:
102272
AN:
152060
Hom.:
37680
Cov.:
32
AF XY:
0.681
AC XY:
50635
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.349
Gnomad4 AMR
AF:
0.756
Gnomad4 ASJ
AF:
0.702
Gnomad4 EAS
AF:
0.960
Gnomad4 SAS
AF:
0.873
Gnomad4 FIN
AF:
0.870
Gnomad4 NFE
AF:
0.780
Gnomad4 OTH
AF:
0.682
Alfa
AF:
0.741
Hom.:
13871
Bravo
AF:
0.648
Asia WGS
AF:
0.852
AC:
2935
AN:
3452

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

NCKAP1-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 16, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJan 31, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.47
Cadd
Benign
2.1
Dann
Benign
0.63
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs9288088; hg19: chr2-183799558; API