19-4543615-G-A

Variant names:

• chr19-4543615-G-A
• rs1344522389
• NM_032108.4:c.2653C>T

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.2653C>T​(p.Pro885Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000185 in 1,081,900 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. P885T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: SEMA6B NM_032108.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.85
• 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=0.14598474).

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.2653C>T	p.Pro885Ser	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.2653C>T	p.Pro885Ser	missense	Exon 17 of 17	ENSP00000467290.1	Q9H3T3-1
	SEMA6B	ENST00000586965.1	TSL:1	c.1852-519C>T		intron	N/A	ENSP00000465722.1	Q9H3T3-3
	SEMA6B	ENST00000676793.2		c.2653C>T	p.Pro885Ser	missense	Exon 17 of 17	ENSP00000503414.1	Q9H3T3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000185 AC: 2 AN: 1081900 Hom.: 0 Cov.: 32 AF XY: 0.00000196 AC XY: 1 AN XY: 511470

African (AFR) AF: 0.00 AC: 0 AN: 23240

American (AMR) AF: 0.00 AC: 0 AN: 9058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14352

East Asian (EAS) AF: 0.0000371 AC: 1 AN: 26942

South Asian (SAS) AF: 0.00 AC: 0 AN: 19960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2966

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 920458

Other (OTH) AF: 0.00 AC: 0 AN: 43666

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.042
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N
PhyloP100		2.9
PrimateAI	Uncertain	0.79	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.14	B
Vest4		0.14
MutPred		0.30		Loss of catalytic residue at P885 (P = 0.0091)
MVP		0.043
MPC		1.9
ClinPred		0.51	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.24
gMVP		0.23
Mutation Taster		=84/16	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: rs1344522389; hg19: chr19-4543627;