19-4543615-G-C

Variant names:

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

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>G​(p.Pro885Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• 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=0.22137237).

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>G	p.Pro885Ala	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>G	p.Pro885Ala	missense	Exon 17 of 17	ENSP00000467290.1	Q9H3T3-1
	SEMA6B	ENST00000586965.1	TSL:1	c.1852-519C>G		intron	N/A	ENSP00000465722.1	Q9H3T3-3
	SEMA6B	ENST00000676793.2		c.2653C>G	p.Pro885Ala	missense	Exon 17 of 17	ENSP00000503414.1	Q9H3T3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000660 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.044
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.9
PrimateAI	Pathogenic	0.79	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.63	P
Vest4		0.29
MutPred		0.25		Loss of catalytic residue at P885 (P = 0.012)
MVP		0.043
MPC		2.1
ClinPred		0.50	T
GERP RS		3.9
Varity_R		0.28
gMVP		0.22
Mutation Taster		=78/22	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;