9-128423242-C-A

Variant names:

• chr9-128423242-C-A
• rs139357437
• NM_016174.5:c.405C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016174.5(CERCAM):​c.405C>A​(p.Asn135Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CERCAM NM_016174.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.349

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10055444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERCAM	NM_016174.5	c.405C>A	p.Asn135Lys	missense_variant	Exon 3 of 13	ENST00000372838.9	NP_057258.3
CERCAM	NM_001286760.1	c.171C>A	p.Asn57Lys	missense_variant	Exon 3 of 13		NP_001273689.1
CERCAM	XM_011518763.4	c.171C>A	p.Asn57Lys	missense_variant	Exon 3 of 13		XP_011517065.1
CERCAM	XM_047423450.1	c.171C>A	p.Asn57Lys	missense_variant	Exon 4 of 14		XP_047279406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERCAM	ENST00000372838.9	c.405C>A	p.Asn135Lys	missense_variant	Exon 3 of 13	1	NM_016174.5	ENSP00000361929.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.405C>A (p.N135K) alteration is located in exon 3 (coding exon 3) of the CERCAM gene. This alteration results from a C to A substitution at nucleotide position 405, causing the asparagine (N) at amino acid position 135 to be replaced by a lysine (K). 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	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.0038	.;.;T;.;T;.;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.54	T;T;T;T;T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-1.4	.;.;.;.;N;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.040	N;N;N;N;N;N;.
REVEL	Benign	0.20
Sift	Benign	0.47	T;T;T;T;T;T;.
Sift4G	Uncertain	0.037	D;T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;B;.;.
Vest4		0.14, 0.14, 0.14
MutPred		0.57		.;.;.;.;Gain of methylation at N135 (P = 0.0186);.;.;
MVP		0.63
MPC		0.15
ClinPred		0.15	T
GERP RS		2.9
Varity_R		0.043
gMVP		0.37

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: rs139357437; hg19: chr9-131185521;