rs372162252
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_133433.4(NIPBL):c.2105C>T(p.Thr702Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000298 in 1,613,442 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )
Consequence
NIPBL
NM_133433.4 missense
NM_133433.4 missense
Scores
1
9
9
Clinical Significance
Conservation
PhyloP100: 4.99
Genes affected
NIPBL (HGNC:28862): (NIPBL cohesin loading factor) This gene encodes the homolog of the Drosophila melanogaster Nipped-B gene product and fungal Scc2-type sister chromatid cohesion proteins. The Drosophila protein facilitates enhancer-promoter communication of remote enhancers and plays a role in developmental regulation. It is also homologous to a family of chromosomal adherins with broad roles in sister chromatid cohesion, chromosome condensation, and DNA repair. The human protein has a bipartite nuclear targeting sequence and a putative HEAT repeat. Condensins, cohesins and other complexes with chromosome-related functions also contain HEAT repeats. Mutations in this gene result in Cornelia de Lange syndrome, a disorder characterized by dysmorphic facial features, growth delay, limb reduction defects, and cognitive disability. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, NIPBL
BP4
?
Computational evidence support a benign effect (MetaRNN=0.016716212).
BP6
?
Variant 5-36985285-C-T is Benign according to our data. Variant chr5-36985285-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436006.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000659 (10/151854) while in subpopulation EAS AF= 0.00173 (9/5188). AF 95% confidence interval is 0.000904. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
High AC in GnomAd at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NIPBL | NM_133433.4 | c.2105C>T | p.Thr702Ile | missense_variant | 10/47 | ENST00000282516.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NIPBL | ENST00000282516.13 | c.2105C>T | p.Thr702Ile | missense_variant | 10/47 | 1 | NM_133433.4 | P1 | |
NIPBL | ENST00000448238.2 | c.2105C>T | p.Thr702Ile | missense_variant | 10/46 | 1 | |||
NIPBL | ENST00000652901.1 | c.2105C>T | p.Thr702Ile | missense_variant | 10/46 | ||||
NIPBL | ENST00000504430.5 | n.1725C>T | non_coding_transcript_exon_variant | 6/8 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000659 AC: 10AN: 151854Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000216 AC: 54AN: 249666Hom.: 0 AF XY: 0.000237 AC XY: 32AN XY: 135224
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GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461588Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19AN XY: 727074
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 12, 2015 | - - |
Cornelia de Lange syndrome 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Aug 15, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Polyphen
P;D
Vest4
MutPred
Loss of phosphorylation at T702 (P = 7e-04);Loss of phosphorylation at T702 (P = 7e-04);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at