19-4543882-C-G

Variant names:

• chr19-4543882-C-G
• rs1977088899
• NM_032108.4:c.2386G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032108.4(SEMA6B):​c.2386G>C​(p.Asp796His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,054,242 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: SEMA6B NM_032108.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2734657).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6B	NM_032108.4	c.2386G>C	p.Asp796His	missense_variant	Exon 17 of 17	ENST00000586582.6	NP_115484.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6B	ENST00000586582.6	c.2386G>C	p.Asp796His	missense_variant	Exon 17 of 17	1	NM_032108.4	ENSP00000467290.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000190 AC: 2 AN: 1054242 Hom.: 0 Cov.: 32 AF XY: 0.00000201 AC XY: 1 AN XY: 497540

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000832

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2386G>C (p.D796H) alteration is located in exon 17 (coding exon 16) of the SEMA6B gene. This alteration results from a G to C substitution at nucleotide position 2386, causing the aspartic acid (D) at amino acid position 796 to be replaced by a histidine (H). 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	Pathogenic	0.63
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PrimateAI	Pathogenic	0.93	D
Sift4G	Benign	0.086	T
Polyphen		1.0	D
Vest4		0.17
MutPred		0.15		Gain of sheet (P = 0.0016);
MVP		0.13
MPC		3.5
ClinPred		0.93	D
GERP RS		3.0
Varity_R		0.22
gMVP		0.56

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

Other links and lift over

dbSNP: rs1977088899; hg19: chr19-4543894;