chr19-4543896-G-C

Variant names:

• chr19-4543896-G-C
• rs1977089420
• NM_032108.4:c.2372C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_032108.4(SEMA6B):​c.2372C>G​(p.Pro791Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000332 in 1,204,242 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SEMA6B NM_032108.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.08
• 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=0.40113962).
• BP6: Variant 19-4543896-G-C is Benign according to our data. Variant chr19-4543896-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1709918.

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.2372C>G	p.Pro791Arg	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.2372C>G	p.Pro791Arg	missense	Exon 17 of 17	ENSP00000467290.1	Q9H3T3-1
	SEMA6B	ENST00000586965.1	TSL:1	c.1851+521C>G		intron	N/A	ENSP00000465722.1	Q9H3T3-3
	SEMA6B	ENST00000676793.2		c.2372C>G	p.Pro791Arg	missense	Exon 17 of 17	ENSP00000503414.1	Q9H3T3-1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000285 AC: 3 AN: 1053064 Hom.: 0 Cov.: 32 AF XY: 0.00000402 AC XY: 2 AN XY: 496970

African (AFR) AF: 0.00 AC: 0 AN: 21740

American (AMR) AF: 0.00 AC: 0 AN: 7478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12832

East Asian (EAS) AF: 0.00 AC: 0 AN: 23874

South Asian (SAS) AF: 0.00 AC: 0 AN: 19294

European-Finnish (FIN) AF: 0.0000484 AC: 1 AN: 20644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2724

European-Non Finnish (NFE) AF: 0.00000111 AC: 1 AN: 902942

Other (OTH) AF: 0.0000241 AC: 1 AN: 41536

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151178 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73818

African (AFR) AF: 0.00 AC: 0 AN: 41320

American (AMR) AF: 0.0000661 AC: 1 AN: 15128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67694

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy, progressive myoclonic, 11 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.1
PrimateAI	Pathogenic	0.92	D
Sift4G	Benign	0.077	T
Polyphen		1.0	D
Vest4		0.41
MutPred		0.30		Gain of MoRF binding (P = 0.0025)
MVP		0.043
MPC		3.3
ClinPred		0.94	D
GERP RS		3.0
Varity_R		0.25
gMVP		0.68
Mutation Taster		=54/46	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: rs1977089420; hg19: chr19-4543908;