2-96860876-C-G

Variant names:

• chr2-96860876-C-G
• rs747244200
• NM_017789.5:c.2252G>C

Variant summary

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

The NM_017789.5(SEMA4C):​c.2252G>C​(p.Arg751Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R751Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: SEMA4C NM_017789.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

Genes affected

SEMA4C (HGNC:10731): (semaphorin 4C) Predicted to enable chemorepellent activity and semaphorin receptor binding activity. Involved in muscle cell differentiation and positive regulation of stress-activated MAPK cascade. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12620541).
• BS2: High AC in GnomAdExome4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4C	NM_017789.5	c.2252G>C	p.Arg751Pro	missense_variant	Exon 15 of 15	ENST00000305476.10	NP_060259.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA4C	ENST00000305476.10	c.2252G>C	p.Arg751Pro	missense_variant	Exon 15 of 15	1	NM_017789.5	ENSP00000306844.5
SEMA4C	ENST00000467747.1	n.2243G>C		non_coding_transcript_exon_variant	Exon 3 of 3	2
SEMA4C	ENST00000474420.1	n.1485G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2
SEMA4C	ENST00000482925.5	n.2642G>C		non_coding_transcript_exon_variant	Exon 13 of 13	2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249344 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1460830 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 726732

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44720

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26130

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52404

Gnomad4 NFE exome AF: 0.0000423 AC: 47 AN: 1111984

Gnomad4 Remaining exome AF: 0.0000662 AC: 4 AN: 60386

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74336

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000441 AC: 0.0000440995 AN: 0.0000440995

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2252G>C (p.R751P) alteration is located in exon 15 (coding exon 14) of the SEMA4C gene. This alteration results from a G to C substitution at nucleotide position 2252, causing the arginine (R) at amino acid position 751 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.070	N
REVEL	Uncertain	0.39
Sift	Benign	0.17	T
Sift4G	Benign	0.29	T
Polyphen		0.12	B
Vest4		0.11
MVP		0.56
MPC		0.46
ClinPred		0.060	T
GERP RS		3.3
Varity_R		0.15
gMVP		0.41
Mutation Taster		=69/31	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

Publications

LitVar

Other links and lift over

dbSNP: rs747244200; hg19: chr2-97526613;