rs8192321

Variant names:

• chr8-22160637-A-G
• rs8192321
• NM_001385654.1:c.-54+782A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001385654.1(SFTPC):​c.-54+782A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 152,006 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.023 (67 hom., cov: 32)
• Consequence: SFTPC NM_001385654.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.143
• Publications: 1 publications found

Genes affected

SFTPC (HGNC:10802): (surfactant protein C) This gene encodes the pulmonary-associated surfactant protein C (SPC), an extremely hydrophobic surfactant protein essential for lung function and homeostasis after birth. Pulmonary surfactant is a surface-active lipoprotein complex composed of 90% lipids and 10% proteins which include plasma proteins and apolipoproteins SPA, SPB, SPC and SPD. The surfactant is secreted by the alveolar cells of the lung and maintains the stability of pulmonary tissue by reducing the surface tension of fluids that coat the lung. Multiple mutations in this gene have been identified, which cause pulmonary surfactant metabolism dysfunction type 2, also called pulmonary alveolar proteinosis due to surfactant protein C deficiency, and are associated with interstitial lung disease in older infants, children, and adults. Alternatively spliced transcript variants encoding different protein isoforms have been identified.[provided by RefSeq, Feb 2010]

SFTPC Gene-Disease associations (from GenCC):

• surfactant metabolism dysfunction, pulmonary, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• chronic respiratory distress with surfactant metabolism deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• SFTPC- related interstitial lung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0233 (3538/152006) while in subpopulation NFE AF = 0.0343 (2329/67952). AF 95% confidence interval is 0.0331. There are 67 homozygotes in GnomAd4. There are 1709 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3538 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPC	NM_001385654.1	c.-54+782A>G		intron_variant	Intron 2 of 7		NP_001372583.1
SFTPC	NM_001385655.1	c.-54+782A>G		intron_variant	Intron 2 of 7		NP_001372584.1
SFTPC	NM_001385656.1	c.-54+782A>G		intron_variant	Intron 2 of 6		NP_001372585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPC	ENST00000524318.3	n.739+782A>G		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3544 AN: 151888 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.00580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00977

Gnomad FIN AF: 0.0330

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0343

Gnomad OTH AF: 0.0278

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0233 AC: 3538 AN: 152006 Hom.: 67 Cov.: 32 AF XY: 0.0230 AC XY: 1709 AN XY: 74310

African (AFR) AF: 0.00579 AC: 240 AN: 41468

American (AMR) AF: 0.0285 AC: 436 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5162

South Asian (SAS) AF: 0.00978 AC: 47 AN: 4806

European-Finnish (FIN) AF: 0.0330 AC: 349 AN: 10564

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.0343 AC: 2329 AN: 67952

Other (OTH) AF: 0.0270 AC: 57 AN: 2112

Alfa AF: 0.0298 Hom.: 124

Bravo AF: 0.0225

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.0
DANN	Benign	0.49
PhyloP100		0.14

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs8192321; hg19: chr8-22018150;