15-32167993-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000746.6(CHRNA7):​c.1044C>T​(p.Pro348Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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

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]

LOC102724078 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 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 id 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.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0254 (3756/147764) while in subpopulation NFE AF= 0.0341 (2239/65700). AF 95% confidence interval is 0.0329. There are 0 homozygotes in gnomad4. There are 1761 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3756 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA7	NM_000746.6	c.1044C>T	p.Pro348Pro	synonymous_variant	Exon 10 of 10	ENST00000306901.9	NP_000737.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA7	ENST00000306901.9	c.1044C>T	p.Pro348Pro	synonymous_variant	Exon 10 of 10	1	NM_000746.6	ENSP00000303727.2

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

GnomAD3 exomes AF: 0.0288 AC: 6701 AN: 232364 Hom.: 1 AF XY: 0.0296 AC XY: 3759 AN XY: 127080

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 SAS exome AF: 0.0352

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

Gnomad4 AFR exome AF: 0.0171

Gnomad4 AMR exome AF: 0.0215

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.00922

Gnomad4 SAS exome AF: 0.0427

Gnomad4 FIN exome AF: 0.0142

Gnomad4 NFE exome AF: 0.0393

Gnomad4 OTH exome AF: 0.0418

GnomAD4 genome AF: 0.0254 AC: 3756 AN: 147764 Hom.: 0 Cov.: 20 AF XY: 0.0244 AC XY: 1761 AN XY: 72266

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.0239

Gnomad4 ASJ AF: 0.0866

Gnomad4 EAS AF: 0.00277

Gnomad4 SAS AF: 0.0307

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.0341

Gnomad4 OTH AF: 0.0323

Alfa AF: 0.0342 Hom.: 0

ExAC AF: 0.0307 AC: 3656

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
GERP RS		-8.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs71653603; hg19: chr15-32460194; COSMIC: COSV60968307; COSMIC: COSV60968307;