chr7-147108277-C-T

Variant names:

• chr7-147108277-C-T
• rs142984073
• NM_014141.6:c.681C>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.681C>T​(p.His227His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,613,666 control chromosomes in the GnomAD database, including 10 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 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (9 hom.)
• Consequence: CNTNAP2 NM_014141.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -2.02
• Publications: 5 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: G2P, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 7-147108277-C-T is Benign according to our data. Variant chr7-147108277-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95577.
• BP7: Synonymous conserved (PhyloP=-2.02 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.681C>T	p.His227His	synonymous	Exon 5 of 24	NP_054860.1	A0A090N7T7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	ENST00000361727.8	TSL:1 MANE Select	c.681C>T	p.His227His	synonymous	Exon 5 of 24	ENSP00000354778.3	Q9UHC6-1
	CNTNAP2	ENST00000636561.1	TSL:5	n.584C>T		non_coding_transcript_exon	Exon 4 of 8
	CNTNAP2	ENST00000636870.1	TSL:5	n.543C>T		non_coding_transcript_exon	Exon 3 of 22

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 152040 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00387

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00278

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00221 AC: 554 AN: 251166 AF XY: 0.00225

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00247

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00204 AC: 2982 AN: 1461508 Hom.: 9 Cov.: 33 AF XY: 0.00216 AC XY: 1569 AN XY: 727052

African (AFR) AF: 0.00281 AC: 94 AN: 33464

American (AMR) AF: 0.00407 AC: 182 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.000804 AC: 21 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39654

South Asian (SAS) AF: 0.00201 AC: 173 AN: 86254

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53404

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5764

European-Non Finnish (NFE) AF: 0.00213 AC: 2373 AN: 1111786

Other (OTH) AF: 0.00200 AC: 121 AN: 60374

GnomAD4 genome AF: 0.00263 AC: 400 AN: 152158 Hom.: 1 Cov.: 32 AF XY: 0.00257 AC XY: 191 AN XY: 74366

African (AFR) AF: 0.00272 AC: 113 AN: 41508

American (AMR) AF: 0.00386 AC: 59 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.00278 AC: 189 AN: 68006

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00224 Hom.: 1

Bravo AF: 0.00296

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00302

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	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	-0.54
CADD	Benign	0.17
DANN	Benign	0.43
PhyloP100		-2.0
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs142984073; hg19: chr7-146805369; COSMIC: COSV105926045;