rs71653603

Variant names:

• chr15-32167993-C-T
• rs71653603
• NM_000746.6:c.1044C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-32167993-C-T
• chr15-32167993-C-A
• chr15-32167993-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000746.6(CHRNA7):​c.1044C>T​(p.Pro348Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (0 hom., cov: 20)
  • Exomes 𝑓: 0.038 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRNA7 NM_000746.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -8.38
• Publications: 6 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

ENSG00000301688 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028790832).
• BP6: Variant 15-32167993-C-T is Benign according to our data. Variant chr15-32167993-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1190190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.38 with no splicing effect.

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.1044C>T	p.Pro348Pro	synonymous	Exon 10 of 10	NP_000737.1	P36544-1
	CHRNA7	NM_001190455.3		c.1131C>T	p.Pro377Pro	synonymous	Exon 10 of 10	NP_001177384.1	P36544-2
	CHRNA7	NR_046324.1		n.966C>T		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA7	ENST00000306901.9	TSL:1 MANE Select	c.1044C>T	p.Pro348Pro	synonymous	Exon 10 of 10	ENSP00000303727.2	P36544-1
	CHRNA7	ENST00000635884.1	TSL:5	c.748C>T	p.Arg250Trp	missense	Exon 9 of 9	ENSP00000489834.1	A0A1B0GTT9
	CHRNA7	ENST00000454250.7	TSL:2	c.1131C>T	p.Pro377Pro	synonymous	Exon 10 of 10	ENSP00000407546.3	P36544-2

Frequencies

GnomAD3 genomes AF: 0.0255 AC: 3758 AN: 147654 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00559

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.0866

Gnomad EAS AF: 0.00276

Gnomad SAS AF: 0.0307

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.0772

Gnomad NFE AF: 0.0341

Gnomad OTH AF: 0.0326

GnomAD2 exomes AF: 0.0288 AC: 6701 AN: 232364 AF XY: 0.0296

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.00186

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.0331

Gnomad OTH exome AF: 0.0342

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0381 AC: 54493 AN: 1430008 Hom.: 0 Cov.: 31 AF XY: 0.0387 AC XY: 27553 AN XY: 711172

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

African (AFR) AF: 0.0171 AC: 569 AN: 33184

American (AMR) AF: 0.0215 AC: 943 AN: 43852

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2778 AN: 24412

East Asian (EAS) AF: 0.00922 AC: 364 AN: 39500

South Asian (SAS) AF: 0.0427 AC: 3602 AN: 84300

European-Finnish (FIN) AF: 0.0142 AC: 748 AN: 52576

Middle Eastern (MID) AF: 0.0571 AC: 313 AN: 5480

European-Non Finnish (NFE) AF: 0.0393 AC: 42711 AN: 1087796

Other (OTH) AF: 0.0418 AC: 2465 AN: 58908

⚠️ 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 AF: 0.0254 AC: 3756 AN: 147764 Hom.: 0 Cov.: 20 AF XY: 0.0244 AC XY: 1761 AN XY: 72266

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

African (AFR) AF: 0.0129 AC: 525 AN: 40744

American (AMR) AF: 0.0239 AC: 354 AN: 14816

Ashkenazi Jewish (ASJ) AF: 0.0866 AC: 271 AN: 3128

East Asian (EAS) AF: 0.00277 AC: 14 AN: 5056

South Asian (SAS) AF: 0.0307 AC: 143 AN: 4656

European-Finnish (FIN) AF: 0.0114 AC: 119 AN: 10452

Middle Eastern (MID) AF: 0.0725 AC: 20 AN: 276

European-Non Finnish (NFE) AF: 0.0341 AC: 2239 AN: 65700

Other (OTH) AF: 0.0323 AC: 66 AN: 2042

⚠️ 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: 0.0342 Hom.: 0

ExAC AF: 0.0307 AC: 3656

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
AlphaMissense	Benign	0.12
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.18
DANN	Benign	0.71
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0029	T
PhyloP100		-8.4
GERP RS		-8.0
Mutation Taster		=99/1	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: rs71653603; hg19: chr15-32460194; COSMIC: COSV60968307; COSMIC: COSV60968307;