9-128424270-C-G

Variant names:

• chr9-128424270-C-G
• rs146651928
• NM_016174.5:c.559C>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_016174.5(CERCAM):​c.559C>G​(p.Gln187Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000908 in 1,613,892 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (2 hom.)
• Consequence: CERCAM NM_016174.5 missense, splice_region
• Scores: Splicing: ADA: 0.4775
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07498148).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERCAM	NM_016174.5	c.559C>G	p.Gln187Glu	missense_variant, splice_region_variant	Exon 4 of 13	ENST00000372838.9	NP_057258.3
CERCAM	NM_001286760.1	c.325C>G	p.Gln109Glu	missense_variant, splice_region_variant	Exon 4 of 13		NP_001273689.1
CERCAM	XM_011518763.4	c.325C>G	p.Gln109Glu	missense_variant, splice_region_variant	Exon 4 of 13		XP_011517065.1
CERCAM	XM_047423450.1	c.325C>G	p.Gln109Glu	missense_variant, splice_region_variant	Exon 5 of 14		XP_047279406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERCAM	ENST00000372838.9	c.559C>G	p.Gln187Glu	missense_variant, splice_region_variant	Exon 4 of 13	1	NM_016174.5	ENSP00000361929.4

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.00101

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000546 AC: 137 AN: 251004 Hom.: 0 AF XY: 0.000575 AC XY: 78 AN XY: 135676

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000943 AC: 1379 AN: 1461674 Hom.: 2 Cov.: 34 AF XY: 0.000908 AC XY: 660 AN XY: 727164

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00119

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000572 AC: 87 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74370

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000386 Hom.: 0

Bravo AF: 0.000657

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000585 AC: 71

EpiCase AF: 0.00136

EpiControl AF: 0.00172

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.559C>G (p.Q187E) alteration is located in exon 4 (coding exon 4) of the CERCAM gene. This alteration results from a C to G substitution at nucleotide position 559, causing the glutamine (Q) at amino acid position 187 to be replaced by a glutamic acid (E). 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	-0.42	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	.;T;.;T;T
Eigen	Benign	0.027
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.074	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;.;.;L;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N;N;N;N;.
REVEL	Benign	0.089
Sift	Benign	0.076	T;D;T;T;.
Sift4G	Benign	0.25	T;D;T;T;T
Polyphen		0.40	.;.;.;B;.
Vest4		0.43
MVP		0.32
MPC		0.61
ClinPred		0.039	T
GERP RS		4.6
Varity_R		0.32
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.48
dbscSNV1_RF	Benign	0.51
SpliceAI score (max)		0.010		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: rs146651928; hg19: chr9-131186549;