11-99819552-A-T

Variant names:

• chr11-99819552-A-T
• rs532915134
• NM_014361.4:c.64A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014361.4(CNTN5):​c.64A>T​(p.Lys22*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 37)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CNTN5 NM_014361.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTN5	NM_014361.4	c.64A>T	p.Lys22*	stop_gained	Exon 4 of 25	ENST00000524871.6	NP_055176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTN5	ENST00000524871.6	c.64A>T	p.Lys22*	stop_gained	Exon 4 of 25	1	NM_014361.4	ENSP00000435637.1

Frequencies

GnomAD3 genomes Cov.: 37

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458224 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725556

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110056

Other (OTH) AF: 0.00 AC: 0 AN: 60268

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 37

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Benign	-0.048
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.52	D
PhyloP100		1.3
Vest4		0.25
GERP RS		-1.2
PromoterAI		0.0099	Neutral
Mutation Taster		=47/153	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs532915134; hg19: chr11-99690283;