chr19-4543752-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_032108.4(SEMA6B):​c.2516C>T​(p.Pro839Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000652 in 1,226,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P839Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: SEMA6B NM_032108.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13955683).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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>T	p.Pro839Leu	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>T	p.Pro839Leu	missense	Exon 17 of 17	ENSP00000467290.1	Q9H3T3-1
	SEMA6B	ENST00000586965.1	TSL:1	c.1852-656C>T		intron	N/A	ENSP00000465722.1	Q9H3T3-3
	SEMA6B	ENST00000676793.2		c.2516C>T	p.Pro839Leu	missense	Exon 17 of 17	ENSP00000503414.1	Q9H3T3-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151954 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000465 AC: 5 AN: 1074144 Hom.: 0 Cov.: 32 AF XY: 0.00000986 AC XY: 5 AN XY: 507200

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

American (AMR) AF: 0.00 AC: 0 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: 0.0000514 AC: 1 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: 0.00000436 AC: 4 AN: 916474

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

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151954 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74222

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.000131 AC: 2 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.66
PrimateAI	Pathogenic	0.90	D
Sift4G	Uncertain	0.039	D
Polyphen		0.0070	B
Vest4		0.11
MutPred		0.25		Loss of loop (P = 0.0073)
MVP		0.043
MPC		3.2
ClinPred		0.87	D
GERP RS		2.7
Varity_R		0.12
gMVP		0.37
Mutation Taster		=93/7	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; COSMIC: COSV104618221; COSMIC: COSV104618221;