rs965407880

Variant names:

• chr19-4543752-G-T
• rs965407880
• NM_032108.4:c.2516C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-4543752-G-T
• chr19-4543752-G-A
• chr19-4543752-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032108.4(SEMA6B):​c.2516C>A​(p.Pro839Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000931 in 1,074,144 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: 9.3e-7 (0 hom.)
• Consequence: SEMA6B NM_032108.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.663
• Publications: 1 publications found

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]

SEMA6B Gene-Disease associations (from GenCC):

• progressive myoclonus epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• epilepsy, progressive myoclonic, 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intellectual disability

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18882963).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032108.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA6B	NM_032108.4	MANE Select	c.2516C>A	p.Pro839Gln	missense	Exon 17 of 17	NP_115484.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA6B	ENST00000586582.6	TSL:1 MANE Select	c.2516C>A	p.Pro839Gln	missense	Exon 17 of 17	ENSP00000467290.1	Q9H3T3-1
	SEMA6B	ENST00000586965.1	TSL:1	c.1852-656C>A		intron	N/A	ENSP00000465722.1	Q9H3T3-3
	SEMA6B	ENST00000676793.2		c.2516C>A	p.Pro839Gln	missense	Exon 17 of 17	ENSP00000503414.1	Q9H3T3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.31e-7 AC: 1 AN: 1074144 Hom.: 0 Cov.: 32 AF XY: 0.00000197 AC XY: 1 AN XY: 507200

African (AFR) AF: 0.00 AC: 0 AN: 22634

American (AMR) AF: 0.000122 AC: 1 AN: 8226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14070

East Asian (EAS) AF: 0.00 AC: 0 AN: 26116

South Asian (SAS) AF: 0.00 AC: 0 AN: 19460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2888

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 916474

Other (OTH) AF: 0.00 AC: 0 AN: 43228

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.66
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.021	D
Polyphen		0.57	P
Vest4		0.20
MutPred		0.18		Loss of loop (P = 0.0073)
MVP		0.043
MPC		3.0
ClinPred		0.88	D
GERP RS		2.7
Varity_R		0.12
gMVP		0.39
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs965407880; hg19: chr19-4543764;