9-128424590-T-G

Variant names:

• chr9-128424590-T-G
• rs756008871
• NM_016174.5:c.742T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016174.5(CERCAM):​c.742T>G​(p.Phe248Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CERCAM NM_016174.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92

Genes affected

CERCAM (HGNC:23723): (cerebral endothelial cell adhesion molecule) Enables identical protein binding activity. Acts upstream of or within cell adhesion. Predicted to be located in endoplasmic reticulum lumen. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERCAM	NM_016174.5	c.742T>G	p.Phe248Val	missense_variant	Exon 5 of 13	ENST00000372838.9	NP_057258.3
CERCAM	NM_001286760.1	c.508T>G	p.Phe170Val	missense_variant	Exon 5 of 13		NP_001273689.1
CERCAM	XM_011518763.4	c.508T>G	p.Phe170Val	missense_variant	Exon 5 of 13		XP_011517065.1
CERCAM	XM_047423450.1	c.508T>G	p.Phe170Val	missense_variant	Exon 6 of 14		XP_047279406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERCAM	ENST00000372838.9	c.742T>G	p.Phe248Val	missense_variant	Exon 5 of 13	1	NM_016174.5	ENSP00000361929.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461834 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.742T>G (p.F248V) alteration is located in exon 5 (coding exon 5) of the CERCAM gene. This alteration results from a T to G substitution at nucleotide position 742, causing the phenylalanine (F) at amino acid position 248 to be replaced by a valine (V). 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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	.;.;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.9	.;.;M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.6	D;D;D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.89
MutPred		0.40		.;.;Loss of helix (P = 0.2022);.;
MVP		0.96
MPC		0.67
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.96

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: rs756008871; hg19: chr9-131186869;