7-147562214-C-T

Variant names:

• chr7-147562214-C-T
• rs61732849
• NM_014141.6:c.1854C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_014141.6(CNTNAP2):​c.1854C>T​(p.Gly618Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,613,984 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G618G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0099 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: CNTNAP2 NM_014141.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.936
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 7-147562214-C-T is Benign according to our data. Variant chr7-147562214-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.936 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00995 (1515/152262) while in subpopulation AFR AF = 0.0345 (1435/41568). AF 95% confidence interval is 0.033. There are 26 homozygotes in GnomAd4. There are 754 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 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.1854C>T	p.Gly618Gly	synonymous	Exon 12 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.1854C>T	p.Gly618Gly	synonymous	Exon 12 of 24	ENSP00000354778.3	Q9UHC6-1
	CNTNAP2	ENST00000636870.1	TSL:5	n.1716C>T		non_coding_transcript_exon	Exon 10 of 22
	CNTNAP2	ENST00000637825.1	TSL:5	n.1337C>T		non_coding_transcript_exon	Exon 9 of 14

Frequencies

GnomAD3 genomes AF: 0.00996 AC: 1515 AN: 152144 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00269 AC: 675 AN: 251290 AF XY: 0.00205

Gnomad AFR exome AF: 0.0353

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00113 AC: 1648 AN: 1461722 Hom.: 24 Cov.: 30 AF XY: 0.000997 AC XY: 725 AN XY: 727178

African (AFR) AF: 0.0361 AC: 1207 AN: 33466

American (AMR) AF: 0.00228 AC: 102 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5762

European-Non Finnish (NFE) AF: 0.000143 AC: 159 AN: 1111900

Other (OTH) AF: 0.00275 AC: 166 AN: 60388

GnomAD4 genome AF: 0.00995 AC: 1515 AN: 152262 Hom.: 26 Cov.: 32 AF XY: 0.0101 AC XY: 754 AN XY: 74438

African (AFR) AF: 0.0345 AC: 1435 AN: 41568

American (AMR) AF: 0.00360 AC: 55 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68022

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00554 Hom.: 8

Bravo AF: 0.0116

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Cortical dysplasia-focal epilepsy syndrome (2)
-	-	2	not provided (2)
-	-	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	-0.24
CADD	Benign	12
DANN	Benign	0.73
PhyloP100		0.94
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: rs61732849; hg19: chr7-147259306;