NM_014141.6:c.3633G>A

Variant names:

• chr7-148383806-G-A
• rs138477292
• NM_014141.6:c.3633G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014141.6(CNTNAP2):​c.3633G>A​(p.Glu1211Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00877 in 1,614,160 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (81 hom.)
• Consequence: CNTNAP2 NM_014141.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.543
• 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: Illumina, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics

ENSG00000287636 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 7-148383806-G-A is Benign according to our data. Variant chr7-148383806-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.543 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00901 (13176/1461858) while in subpopulation SAS AF = 0.0168 (1451/86254). AF 95% confidence interval is 0.0161. There are 81 homozygotes in GnomAdExome4. There are 6778 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.3633G>A	p.Glu1211Glu	synonymous	Exon 22 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.3633G>A	p.Glu1211Glu	synonymous	Exon 22 of 24	ENSP00000354778.3
	CNTNAP2	ENST00000463592.3	TSL:1	c.-37G>A		5_prime_UTR	Exon 2 of 4	ENSP00000486292.1
	CNTNAP2	ENST00000628930.2	TSL:2	c.810G>A	p.Glu270Glu	synonymous	Exon 7 of 9	ENSP00000487516.1

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 974 AN: 152184 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00974

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00791 AC: 1987 AN: 251270 AF XY: 0.00896

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00753

Gnomad NFE exome AF: 0.00994

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00901 AC: 13176 AN: 1461858 Hom.: 81 Cov.: 33 AF XY: 0.00932 AC XY: 6778 AN XY: 727228

African (AFR) AF: 0.00119 AC: 40 AN: 33480

American (AMR) AF: 0.00226 AC: 101 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0168 AC: 1451 AN: 86254

European-Finnish (FIN) AF: 0.00856 AC: 457 AN: 53394

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5768

European-Non Finnish (NFE) AF: 0.00950 AC: 10562 AN: 1112008

Other (OTH) AF: 0.00778 AC: 470 AN: 60396

GnomAD4 genome AF: 0.00640 AC: 975 AN: 152302 Hom.: 12 Cov.: 33 AF XY: 0.00620 AC XY: 462 AN XY: 74486

African (AFR) AF: 0.00166 AC: 69 AN: 41562

American (AMR) AF: 0.00255 AC: 39 AN: 15296

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0161 AC: 78 AN: 4832

European-Finnish (FIN) AF: 0.00650 AC: 69 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00976 AC: 664 AN: 68030

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00844 Hom.: 3

Bravo AF: 0.00551

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.00871

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Cortical dysplasia-focal epilepsy syndrome (2)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.9
DANN	Benign	0.57
PhyloP100		0.54
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: rs138477292; hg19: chr7-148080898; COSMIC: COSV105926238;