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GeneBe

19-4543954-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032108.4(SEMA6B):c.2314G>A(p.Gly772Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,201,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G772A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

SEMA6B
NM_032108.4 missense

Scores

1
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.45
Variant links:
Genes affected
SEMA6B (HGNC:10739): (semaphorin 6B) This gene encodes a member of the semaphorin family, a group of proteins characterized by the presence of a conserved semaphorin (sema) domain. Whereas some semaphorins are transmembrane proteins, others are secreted. Semaphorins play a major role in axon guidance. The protein encoded by this gene may be involved in both peripheral and central nervous system development. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.038294017).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SEMA6BNM_032108.4 linkuse as main transcriptc.2314G>A p.Gly772Ser missense_variant 17/17 ENST00000586582.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SEMA6BENST00000586582.6 linkuse as main transcriptc.2314G>A p.Gly772Ser missense_variant 17/171 NM_032108.4 P1Q9H3T3-1
SEMA6BENST00000586965.1 linkuse as main transcriptc.1851+463G>A intron_variant 1 Q9H3T3-3
SEMA6BENST00000676793.1 linkuse as main transcriptc.2314G>A p.Gly772Ser missense_variant 17/17 P1Q9H3T3-1
SEMA6BENST00000677828.1 linkuse as main transcriptc.*1576G>A 3_prime_UTR_variant, NMD_transcript_variant 17/17

Frequencies

GnomAD3 genomes
AF:
0.00000662
AC:
1
AN:
150954
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000190
AC:
2
AN:
1050738
Hom.:
0
Cov.:
32
AF XY:
0.00000202
AC XY:
1
AN XY:
495820
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000426
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000111
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000662
AC:
1
AN:
150954
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
73694
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 25, 2023The c.2314G>A (p.G772S) alteration is located in exon 17 (coding exon 16) of the SEMA6B gene. This alteration results from a G to A substitution at nucleotide position 2314, causing the glycine (G) at amino acid position 772 to be replaced by a serine (S). 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
0.079
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.81
Cadd
Benign
0.68
Dann
Benign
0.94
DEOGEN2
Benign
0.038
T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.019
N
LIST_S2
Benign
0.29
T
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.038
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.34
N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Pathogenic
0.82
D
Sift4G
Benign
0.66
T
Polyphen
0.0010
B
Vest4
0.043
MutPred
0.17
Gain of glycosylation at G772 (P = 0.0012);
MVP
0.043
MPC
1.7
ClinPred
0.10
T
GERP RS
0.35
Varity_R
0.029
gMVP
0.24

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: rs1222889210; hg19: chr19-4543966; API