rs983460534

Variant names:

• chr19-4542981-C-A
• rs983460534
• ENST00000586965.1:c.1967G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-4542981-C-A
• chr19-4542981-C-G
• chr19-4542981-C-T

Variant summary

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

The ENST00000586965.1(SEMA6B):​c.1967G>T​(p.Arg656Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000366 in 546,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict 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. R656H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: SEMA6B ENST00000586965.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 0 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=0.09325135).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000586965.1. 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.*620G>T		3_prime_UTR	Exon 17 of 17	NP_115484.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA6B	ENST00000586965.1	TSL:1	c.1967G>T	p.Arg656Leu	missense	Exon 17 of 17	ENSP00000465722.1	Q9H3T3-3
	SEMA6B	ENST00000586582.6	TSL:1 MANE Select	c.*620G>T		3_prime_UTR	Exon 17 of 17	ENSP00000467290.1	Q9H3T3-1
	SEMA6B	ENST00000676793.2		c.*620G>T		3_prime_UTR	Exon 17 of 17	ENSP00000503414.1	Q9H3T3-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000366 AC: 2 AN: 546638 Hom.: 0 Cov.: 0 AF XY: 0.00000338 AC XY: 1 AN XY: 295748

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000128 AC: 2 AN: 15674

American (AMR) AF: 0.00 AC: 0 AN: 34652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19952

East Asian (EAS) AF: 0.00 AC: 0 AN: 32028

South Asian (SAS) AF: 0.00 AC: 0 AN: 62618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2442

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 315408

Other (OTH) AF: 0.00 AC: 0 AN: 30314

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.1
DANN	Benign	0.87
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.093	T
PhyloP100		-1.2
Sift4G	Pathogenic	0.0	D
Vest4		0.17
MVP		0.33
GERP RS		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs983460534; hg19: chr19-4542993;