chr11-99845159-T-G

Position:

• chr11-99845159-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014361.4(CNTN5):​c.474T>G​(p.Ile158Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00768 in 1,613,768 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (85 hom.)
• Consequence: CNTN5 NM_014361.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.168

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013951659).
• BP6: Variant 11-99845159-T-G is Benign according to our data. Variant chr11-99845159-T-G is described in ClinVar as [Benign]. Clinvar id is 720168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN5	NM_014361.4	c.474T>G	p.Ile158Met	missense_variant	6/25	ENST00000524871.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN5	ENST00000524871.6	c.474T>G	p.Ile158Met	missense_variant	6/25	1	NM_014361.4	P1

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 782 AN: 152074 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00434

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00881

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00539 AC: 1344 AN: 249232 Hom.: 13 AF XY: 0.00567 AC XY: 767 AN XY: 135214

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.00557

Gnomad NFE exome AF: 0.00914

Gnomad OTH exome AF: 0.00611

GnomAD4 exome AF: 0.00795 AC: 11616 AN: 1461576 Hom.: 85 Cov.: 32 AF XY: 0.00757 AC XY: 5504 AN XY: 727072

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00318

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00132

Gnomad4 FIN exome AF: 0.00676

Gnomad4 NFE exome AF: 0.00939

Gnomad4 OTH exome AF: 0.00861

GnomAD4 genome AF: 0.00514 AC: 782 AN: 152192 Hom.: 6 Cov.: 32 AF XY: 0.00474 AC XY: 353 AN XY: 74424

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00434

Gnomad4 NFE AF: 0.00881

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00735 Hom.: 9

Bravo AF: 0.00490

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00189 AC: 7

ESP6500EA AF: 0.00694 AC: 57

ExAC AF: 0.00564 AC: 681

EpiCase AF: 0.00851

EpiControl AF: 0.00818

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CNTN5-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 2019

This variant is classified as 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	Benign	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T;T;.;T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.86	D;.;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.014	T;T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.7	L;L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	N;N;N;N;N;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0080	D;D;D;D;T;.
Sift4G	Uncertain	0.051	T;T;T;D;T;D
Polyphen		1.0	.;D;D;D;.;.
Vest4		0.41
MVP		0.72
MPC		0.049
ClinPred		0.047	T
GERP RS		0.25
Varity_R		0.23
gMVP		0.58

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: rs61749255; hg19: chr11-99715891;