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GeneBe

2-96861062-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_017789.5(SEMA4C):c.2066G>A(p.Arg689Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SEMA4C
NM_017789.5 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.87
Variant links:
Genes affected
SEMA4C (HGNC:10731): (semaphorin 4C) Predicted to enable chemorepellent activity and semaphorin receptor binding activity. Involved in muscle cell differentiation and positive regulation of stress-activated MAPK cascade. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP2
Missense variant where missense usually causes diseases, SEMA4C
BP4
Computational evidence support a benign effect (MetaRNN=0.19893724).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SEMA4CNM_017789.5 linkuse as main transcriptc.2066G>A p.Arg689Gln missense_variant 15/15 ENST00000305476.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SEMA4CENST00000305476.10 linkuse as main transcriptc.2066G>A p.Arg689Gln missense_variant 15/151 NM_017789.5 P1
SEMA4CENST00000467747.1 linkuse as main transcriptn.2057G>A non_coding_transcript_exon_variant 3/32
SEMA4CENST00000474420.1 linkuse as main transcriptn.1299G>A non_coding_transcript_exon_variant 2/22
SEMA4CENST00000482925.5 linkuse as main transcriptn.2456G>A non_coding_transcript_exon_variant 13/132

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152182
Hom.:
0
Cov.:
33
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000403
AC:
1
AN:
248274
Hom.:
0
AF XY:
0.00000741
AC XY:
1
AN XY:
135006
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
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:
0.00000274
AC:
4
AN:
1460544
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726544
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152300
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000825
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 08, 2023The c.2066G>A (p.R689Q) alteration is located in exon 15 (coding exon 14) of the SEMA4C gene. This alteration results from a G to A substitution at nucleotide position 2066, causing the arginine (R) at amino acid position 689 to be replaced by a glutamine (Q). 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
0.11
BayesDel_addAF
Benign
-0.055
T
BayesDel_noAF
Benign
-0.22
Cadd
Uncertain
25
Dann
Pathogenic
1.0
DEOGEN2
Benign
0.15
T
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.93
D
M_CAP
Benign
0.042
D
MetaRNN
Benign
0.20
T
MetaSVM
Benign
-0.40
T
MutationAssessor
Benign
0.55
N
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.28
Sift
Benign
0.16
T
Sift4G
Benign
0.24
T
Polyphen
0.91
P
Vest4
0.34
MutPred
0.23
Loss of MoRF binding (P = 0.0301);
MVP
0.67
MPC
0.72
ClinPred
0.76
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.11
gMVP
0.49

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: rs576033097; hg19: chr2-97526799; API