chr12-54500536-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

The NM_005337.5(NCKAP1L):​c.217C>T​(p.His73Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,607,772 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

NCKAP1L
NM_005337.5 missense

Scores

5
14

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.00
Variant links:
Genes affected
NCKAP1L (HGNC:4862): (NCK associated protein 1 like) This gene encodes a member of the HEM family of tissue-specific transmembrane proteins which are highly conserved from invertebrates through mammals. This gene is only expressed in hematopoietic cells. The encoded protein is a part of the Scar/WAVE complex which plays an important role in regulating cell shape in both metazoans and plants. Alternatively spliced transcript variants encoding different isoforms have been found.[provided by RefSeq, May 2010]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.009924024).
BP6
Variant 12-54500536-C-T is Benign according to our data. Variant chr12-54500536-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2054556.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00019 (29/152296) while in subpopulation EAS AF= 0.00559 (29/5188). AF 95% confidence interval is 0.004. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NCKAP1LNM_005337.5 linkuse as main transcriptc.217C>T p.His73Tyr missense_variant 3/31 ENST00000293373.11 NP_005328.2
NCKAP1LNM_001184976.2 linkuse as main transcriptc.67C>T p.His23Tyr missense_variant 3/31 NP_001171905.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NCKAP1LENST00000293373.11 linkuse as main transcriptc.217C>T p.His73Tyr missense_variant 3/311 NM_005337.5 ENSP00000293373 P1P55160-1
NCKAP1LENST00000545638.2 linkuse as main transcriptc.67C>T p.His23Tyr missense_variant 3/312 ENSP00000445596 P55160-2
NCKAP1LENST00000547500.1 linkuse as main transcriptn.241C>T non_coding_transcript_exon_variant 3/32
NCKAP1LENST00000548221.5 linkuse as main transcriptc.217C>T p.His73Tyr missense_variant, NMD_transcript_variant 3/312 ENSP00000447246

Frequencies

GnomAD3 genomes
AF:
0.000191
AC:
29
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00558
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000330
AC:
83
AN:
251296
Hom.:
0
AF XY:
0.000339
AC XY:
46
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00446
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000111
AC:
162
AN:
1455476
Hom.:
0
Cov.:
28
AF XY:
0.000106
AC XY:
77
AN XY:
724554
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00368
Gnomad4 SAS exome
AF:
0.0000697
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000150
GnomAD4 genome
AF:
0.000190
AC:
29
AN:
152296
Hom.:
0
Cov.:
32
AF XY:
0.000188
AC XY:
14
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00559
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000367
Hom.:
0
Bravo
AF:
0.000230
ExAC
AF:
0.000313
AC:
38

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 13, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.091
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.44
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.29
T;.
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.78
T;T
M_CAP
Benign
0.0095
T
MetaRNN
Benign
0.0099
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L;.
MutationTaster
Benign
0.95
D;D
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-1.9
N;N
REVEL
Benign
0.067
Sift
Benign
0.062
T;T
Sift4G
Benign
0.60
T;T
Polyphen
0.93
P;.
Vest4
0.34
MVP
0.068
MPC
0.50
ClinPred
0.13
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.30
gMVP
0.29

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: rs117605527; hg19: chr12-54894320; COSMIC: COSV53210729; COSMIC: COSV53210729; API