2-96860976-G-C

Variant names:

• chr2-96860976-G-C
• rs768050355
• NM_017789.5:c.2152C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017789.5(SEMA4C):​c.2152C>G​(p.Pro718Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 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. P718T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SEMA4C NM_017789.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06374988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4C	NM_017789.5	c.2152C>G	p.Pro718Ala	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.2152C>G	p.Pro718Ala	missense_variant	Exon 15 of 15	1	NM_017789.5	ENSP00000306844.5
SEMA4C	ENST00000467747.1	n.2143C>G		non_coding_transcript_exon_variant	Exon 3 of 3	2
SEMA4C	ENST00000474420.1	n.1385C>G		non_coding_transcript_exon_variant	Exon 2 of 2	2
SEMA4C	ENST00000482925.5	n.2542C>G		non_coding_transcript_exon_variant	Exon 13 of 13	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460690 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726640

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

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44722

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

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: 52246

Gnomad4 NFE exome AF: 8.99e-7 AC: 1 AN: 1111998

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2152C>G (p.P718A) alteration is located in exon 15 (coding exon 14) of the SEMA4C gene. This alteration results from a C to G substitution at nucleotide position 2152, causing the proline (P) at amino acid position 718 to be replaced by an alanine (A). 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	0.061
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.74
DEOGEN2	Benign	0.080	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.81	L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.091
Sift	Benign	0.33	T
Sift4G	Benign	0.88	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.24		Loss of glycosylation at P718 (P = 0.0239);
MVP		0.24
MPC		0.28
ClinPred		0.084	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.35
Mutation Taster		=80/20	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: rs768050355; hg19: chr2-97526713; COSMIC: COSV59691647; COSMIC: COSV59691647;