11-100061213-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_014361.4(CNTN5):c.982C>G(p.Pro328Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000932 in 1,605,812 control chromosomes in the GnomAD database, including 5 homozygotes. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P328S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00076 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (3 hom.)
• Consequence: CNTN5 NM_014361.4 missense, splice_region
• Scores: Splicing: ADA: 0.9767
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.91

Genes affected

CNTN5 (HGNC:2175): (contactin 5) The protein encoded by this gene is a member of the immunoglobulin superfamily, and contactin family, which mediate cell surface interactions during nervous system development. This protein is a glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein that functions as a cell adhesion molecule. It may play a role in the formation of axon connections in the developing nervous system. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

LOC105369456 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 11-100061213-C-G is Benign according to our data. Variant chr11-100061213-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3039934.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN5	NM_014361.4	c.982C>G	p.Pro328Ala	missense_variant, splice_region_variant	10/25	ENST00000524871.6
LOC105369456	XR_947948.3	n.208-5683G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN5	ENST00000524871.6	c.982C>G	p.Pro328Ala	missense_variant, splice_region_variant	10/25	1	NM_014361.4	P1

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152060 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000851 AC: 211 AN: 247854 Hom.: 1 AF XY: 0.000930 AC XY: 125 AN XY: 134438

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00223

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000950 AC: 1381 AN: 1453634 Hom.: 3 Cov.: 31 AF XY: 0.000959 AC XY: 692 AN XY: 721836

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00221

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.000600

GnomAD4 genome AF: 0.000756 AC: 115 AN: 152178 Hom.: 2 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74390

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000960 Hom.: 0

Bravo AF: 0.000593

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00145 AC: 12

ExAC AF: 0.000935 AC: 113

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CNTN5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.4	M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.6	D;D;D;D;.;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D;.;.
Vest4		0.94
MVP		0.91
MPC		0.26
ClinPred		0.39	T
GERP RS		5.3
Varity_R		0.83
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.75
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: rs201910584; hg19: chr11-99931945; COSMIC: COSV54330963;