2-96860840-G-A

Variant names:

• chr2-96860840-G-A
• rs149552418
• NM_017789.5:c.2288C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_017789.5(SEMA4C):​c.2288C>T​(p.Pro763Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,184 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SEMA4C NM_017789.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.00

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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05662638).
• BS2: High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4C	NM_017789.5	c.2288C>T	p.Pro763Leu	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.2288C>T	p.Pro763Leu	missense_variant	Exon 15 of 15	1	NM_017789.5	ENSP00000306844.5
SEMA4C	ENST00000467747.1	n.2279C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2
SEMA4C	ENST00000474420.1	n.1521C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2
SEMA4C	ENST00000482925.5	n.2678C>T		non_coding_transcript_exon_variant	Exon 13 of 13	2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000603

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000400 AC: 10 AN: 249980 AF XY: 0.0000295

Gnomad AFR exome AF: 0.000625

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1460956 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 726800

Gnomad4 AFR exome AF: 0.000597 AC: 20 AN: 33480

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

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26128

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

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52536

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1111986

Gnomad4 Remaining exome AF: 0.0000331 AC: 2 AN: 60382

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74366

Gnomad4 AFR AF: 0.000603 AC: 0.000603049 AN: 0.000603049

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: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2288C>T (p.P763L) alteration is located in exon 15 (coding exon 14) of the SEMA4C gene. This alteration results from a C to T substitution at nucleotide position 2288, causing the proline (P) at amino acid position 763 to be replaced by a leucine (L). 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	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.17
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.011	D
Polyphen		0.058	B
Vest4		0.26
MVP		0.21
MPC		0.30
ClinPred		0.069	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.26
Mutation Taster		=89/11	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: rs149552418; hg19: chr2-97526577;