rs8192339

Variant names:

• chr8-22161558-G-A
• rs8192339
• NM_001385654.1:c.-53-218G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001385654.1(SFTPC):​c.-53-218G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0594 in 876,452 control chromosomes in the GnomAD database, including 2,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (405 hom., cov: 32)
  • Exomes 𝑓: 0.061 (1672 hom.)
• Consequence: SFTPC NM_001385654.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.254
• Publications: 0 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):

• SFTPC-related interstitial lung disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 8-22161558-G-A is Benign according to our data. Variant chr8-22161558-G-A is described in ClinVar as Benign. ClinVar VariationId is 1221063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0646 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385654.1. 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
	SFTPC	NM_001385654.1		c.-53-218G>A		intron	N/A	NP_001372583.1	A0A0S2Z4Q0
	SFTPC	NM_001385655.1		c.-53-218G>A		intron	N/A	NP_001372584.1	A0A0S2Z4Q0
	SFTPC	NM_001385656.1		c.-53-218G>A		intron	N/A	NP_001372585.1	P11686-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPC	ENST00000524318.3	TSL:3	n.740-218G>A		intron	N/A
	SFTPC	ENST00000679463.1	MANE Select	c.-271G>A		upstream_gene	N/A	ENSP00000505152.1	P11686-2
	SFTPC	ENST00000318561.7	TSL:1	c.-271G>A		upstream_gene	N/A	ENSP00000316152.3	P11686-1

Frequencies

GnomAD3 genomes AF: 0.0525 AC: 7995 AN: 152166 Hom.: 405 Cov.: 32

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.0358

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0277

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0662

Gnomad OTH AF: 0.0354

GnomAD4 exome AF: 0.0609 AC: 44110 AN: 724168 Hom.: 1672 AF XY: 0.0595 AC XY: 21764 AN XY: 366050

African (AFR) AF: 0.00889 AC: 152 AN: 17094

American (AMR) AF: 0.0304 AC: 545 AN: 17942

Ashkenazi Jewish (ASJ) AF: 0.0263 AC: 379 AN: 14432

East Asian (EAS) AF: 0.00288 AC: 83 AN: 28848

South Asian (SAS) AF: 0.0311 AC: 1619 AN: 52052

European-Finnish (FIN) AF: 0.161 AC: 3961 AN: 24618

Middle Eastern (MID) AF: 0.0219 AC: 53 AN: 2416

European-Non Finnish (NFE) AF: 0.0666 AC: 35509 AN: 532824

Other (OTH) AF: 0.0533 AC: 1809 AN: 33942

GnomAD4 genome AF: 0.0525 AC: 7989 AN: 152284 Hom.: 405 Cov.: 32 AF XY: 0.0576 AC XY: 4289 AN XY: 74454

African (AFR) AF: 0.0116 AC: 483 AN: 41572

American (AMR) AF: 0.0356 AC: 545 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 96 AN: 3472

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5180

South Asian (SAS) AF: 0.0275 AC: 133 AN: 4830

European-Finnish (FIN) AF: 0.191 AC: 2023 AN: 10598

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0662 AC: 4500 AN: 68012

Other (OTH) AF: 0.0350 AC: 74 AN: 2114

Alfa AF: 0.0611 Hom.: 99

Bravo AF: 0.0390

Asia WGS AF: 0.0180 AC: 61 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.64
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		0.25
PromoterAI		0.033	Neutral

Splicing

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

Other links and lift over

dbSNP: rs8192339; hg19: chr8-22019071;