NM_014141.6:c.1311C>T

Variant names:

• chr7-147132472-C-T
• rs56356283
• NM_014141.6:c.1311C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_014141.6(CNTNAP2):​c.1311C>T​(p.Ile437Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,613,648 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (12 hom.)
• Consequence: CNTNAP2 NM_014141.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 0.867
• Publications: 2 publications found

Genes affected

CNTNAP2 (HGNC:13830): (contactin associated protein 2) This gene encodes a member of the neurexin family which functions in the vertebrate nervous system as cell adhesion molecules and receptors. This protein, like other neurexin proteins, contains epidermal growth factor repeats and laminin G domains. In addition, it includes an F5/8 type C domain, discoidin/neuropilin- and fibrinogen-like domains, thrombospondin N-terminal-like domains and a putative PDZ binding site. This protein is localized at the juxtaparanodes of myelinated axons, and mediates interactions between neurons and glia during nervous system development and is also involved in localization of potassium channels within differentiating axons. This gene encompasses almost 1.5% of chromosome 7 and is one of the largest genes in the human genome. It is directly bound and regulated by forkhead box protein P2, a transcription factor related to speech and language development. This gene has been implicated in multiple neurodevelopmental disorders, including Gilles de la Tourette syndrome, schizophrenia, epilepsy, autism, ADHD and intellectual disability. [provided by RefSeq, Jul 2017]

CNTNAP2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE, NO_KNOWN Submitted by: ClinGen
• cortical dysplasia-focal epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 7-147132472-C-T is Benign according to our data. Variant chr7-147132472-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166910.
• BP7: Synonymous conserved (PhyloP=0.867 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014141.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	NM_014141.6	MANE Select	c.1311C>T	p.Ile437Ile	synonymous	Exon 8 of 24	NP_054860.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	ENST00000361727.8	TSL:1 MANE Select	c.1311C>T	p.Ile437Ile	synonymous	Exon 8 of 24	ENSP00000354778.3
	CNTNAP2	ENST00000636561.1	TSL:5	n.1214C>T		non_coding_transcript_exon	Exon 7 of 8
	CNTNAP2	ENST00000636870.1	TSL:5	n.1173C>T		non_coding_transcript_exon	Exon 6 of 22

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 507 AN: 152120 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00494

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00343 AC: 862 AN: 251146 AF XY: 0.00364

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00896

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00348 AC: 5082 AN: 1461410 Hom.: 12 Cov.: 32 AF XY: 0.00370 AC XY: 2688 AN XY: 727010

African (AFR) AF: 0.000508 AC: 17 AN: 33452

American (AMR) AF: 0.000918 AC: 41 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00410 AC: 354 AN: 86254

European-Finnish (FIN) AF: 0.00974 AC: 520 AN: 53410

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5762

European-Non Finnish (NFE) AF: 0.00356 AC: 3962 AN: 1111712

Other (OTH) AF: 0.00285 AC: 172 AN: 60366

GnomAD4 genome AF: 0.00332 AC: 506 AN: 152238 Hom.: 4 Cov.: 32 AF XY: 0.00330 AC XY: 246 AN XY: 74440

African (AFR) AF: 0.000481 AC: 20 AN: 41562

American (AMR) AF: 0.00268 AC: 41 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4824

European-Finnish (FIN) AF: 0.00847 AC: 90 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00494 AC: 336 AN: 67998

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00350 Hom.: 0

Bravo AF: 0.00257

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.00387

EpiControl AF: 0.00249

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	1	1	Cortical dysplasia-focal epilepsy syndrome (2)
-	-	1	CNTNAP2-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	Pitt-Hopkins-like syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.2
DANN	Benign	0.75
PhyloP100		0.87
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs56356283; hg19: chr7-146829564;