rs200648754

Variant names:

• chr15-32101299-G-T
• rs200648754
• NM_000746.6:c.196-4G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-32101299-G-T
• chr15-32101299-G-A
• chr15-32101299-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000746.6(CHRNA7):​c.196-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (0 hom., cov: 18)
  • Exomes 𝑓: 0.0035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRNA7 NM_000746.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002205
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.331
• Publications: 1 publications found

Genes affected

CHRNA7 (HGNC:1960): (cholinergic receptor nicotinic alpha 7 subunit) The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are thought to be hetero-pentamers composed of homologous subunits. The proposed structure for each subunit is a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region. The protein encoded by this gene forms a homo-oligomeric channel, displays marked permeability to calcium ions and is a major component of brain nicotinic receptors that are blocked by, and highly sensitive to, alpha-bungarotoxin. Once this receptor binds acetylcholine, it undergoes an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. This gene is located in a region identified as a major susceptibility locus for juvenile myoclonic epilepsy and a chromosomal location involved in the genetic transmission of schizophrenia. An evolutionarily recent partial duplication event in this region results in a hybrid containing sequence from this gene and a novel FAM7A gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

CHRNA7 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• epilepsy

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-32101299-G-T is Benign according to our data. Variant chr15-32101299-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 776869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000746.6. 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
	CHRNA7	NM_000746.6	MANE Select	c.196-4G>T		splice_region intron	N/A	NP_000737.1	P36544-1
	CHRNA7	NM_001190455.3		c.283-4G>T		splice_region intron	N/A	NP_001177384.1	P36544-2
	CHRNA7	NR_046324.1		n.308-4G>T		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA7	ENST00000306901.9	TSL:1 MANE Select	c.196-4G>T		splice_region intron	N/A	ENSP00000303727.2	P36544-1
	CHRNA7	ENST00000635759.1	TSL:1	n.61-4G>T		splice_region intron	N/A	ENSP00000489825.1	A0A1B0GTT0
	CHRNA7	ENST00000637786.2	TSL:1	n.196-4G>T		splice_region intron	N/A	ENSP00000490015.1	A0A1B0GU93

Frequencies

GnomAD3 genomes AF: 0.00588 AC: 397 AN: 67556 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.00407

Gnomad AMI AF: 0.0155

Gnomad AMR AF: 0.00534

Gnomad ASJ AF: 0.00436

Gnomad EAS AF: 0.00746

Gnomad SAS AF: 0.00614

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0133

Gnomad NFE AF: 0.00601

Gnomad OTH AF: 0.00776

GnomAD2 exomes AF: 0.00769 AC: 575 AN: 74748 AF XY: 0.00699

Gnomad AFR exome AF: 0.00526

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.00602

Gnomad EAS exome AF: 0.0220

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.00556

Gnomad OTH exome AF: 0.00909

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00354 AC: 3123 AN: 882590 Hom.: 0 Cov.: 34 AF XY: 0.00353 AC XY: 1545 AN XY: 437474

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

African (AFR) AF: 0.00337 AC: 68 AN: 20158

American (AMR) AF: 0.0155 AC: 258 AN: 16620

Ashkenazi Jewish (ASJ) AF: 0.00498 AC: 79 AN: 15860

East Asian (EAS) AF: 0.00649 AC: 174 AN: 26810

South Asian (SAS) AF: 0.0108 AC: 407 AN: 37666

European-Finnish (FIN) AF: 0.0111 AC: 353 AN: 31866

Middle Eastern (MID) AF: 0.00159 AC: 5 AN: 3152

European-Non Finnish (NFE) AF: 0.00238 AC: 1650 AN: 692634

Other (OTH) AF: 0.00341 AC: 129 AN: 37824

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00589 AC: 398 AN: 67586 Hom.: 0 Cov.: 18 AF XY: 0.00670 AC XY: 218 AN XY: 32538

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

African (AFR) AF: 0.00412 AC: 80 AN: 19438

American (AMR) AF: 0.00533 AC: 39 AN: 7322

Ashkenazi Jewish (ASJ) AF: 0.00436 AC: 7 AN: 1606

East Asian (EAS) AF: 0.00751 AC: 17 AN: 2264

South Asian (SAS) AF: 0.00618 AC: 13 AN: 2102

European-Finnish (FIN) AF: 0.0129 AC: 49 AN: 3800

Middle Eastern (MID) AF: 0.0141 AC: 2 AN: 142

European-Non Finnish (NFE) AF: 0.00601 AC: 178 AN: 29622

Other (OTH) AF: 0.00776 AC: 7 AN: 902

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00120 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.2
DANN	Benign	0.75
PhyloP100		-0.33
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
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: rs200648754; hg19: chr15-32393502; COSMIC: COSV60972272;