chr8-22159419-G-T

Variant names:

• chr8-22159419-G-T
• rs8192335
• NM_001385654.1:c.-434-56G>T

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.-434-56G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 298,440 control chromosomes in the GnomAD database, including 41 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 0.011 (14 hom., cov: 32)
  • Exomes 𝑓: 0.013 (27 hom.)
• Consequence: SFTPC NM_001385654.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0700
• 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):

• 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, PanelApp Australia, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0114 (1743/152288) while in subpopulation NFE AF = 0.0187 (1270/68028). AF 95% confidence interval is 0.0178. There are 14 homozygotes in GnomAd4. There are 825 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1743 AD gene.

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.-434-56G>T		intron	N/A	NP_001372583.1	A0A0S2Z4Q0
	SFTPC	NM_001385655.1		c.-434-56G>T		intron	N/A	NP_001372584.1	A0A0S2Z4Q0
	SFTPC	NM_001385656.1		c.-434-56G>T		intron	N/A	NP_001372585.1	P11686-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPC	ENST00000522880.1	TSL:3	n.764-56G>T		intron	N/A
	SFTPC	ENST00000524318.3	TSL:3	n.359-56G>T		intron	N/A
	SFTPC	ENST00000524350.1	TSL:4	n.214-56G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1744 AN: 152170 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.0127 AC: 1850 AN: 146152 Hom.: 27 AF XY: 0.0109 AC XY: 873 AN XY: 80446

African (AFR) AF: 0.00183 AC: 4 AN: 2184

American (AMR) AF: 0.0108 AC: 51 AN: 4704

Ashkenazi Jewish (ASJ) AF: 0.00343 AC: 11 AN: 3204

East Asian (EAS) AF: 0.00 AC: 0 AN: 2416

South Asian (SAS) AF: 0.00330 AC: 108 AN: 32692

European-Finnish (FIN) AF: 0.00461 AC: 35 AN: 7596

Middle Eastern (MID) AF: 0.0165 AC: 9 AN: 544

European-Non Finnish (NFE) AF: 0.0178 AC: 1523 AN: 85710

Other (OTH) AF: 0.0153 AC: 109 AN: 7102

GnomAD4 genome AF: 0.0114 AC: 1743 AN: 152288 Hom.: 14 Cov.: 32 AF XY: 0.0111 AC XY: 825 AN XY: 74452

African (AFR) AF: 0.00322 AC: 134 AN: 41566

American (AMR) AF: 0.0148 AC: 226 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00374 AC: 18 AN: 4816

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10614

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0187 AC: 1270 AN: 68028

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0133 Hom.: 4

Bravo AF: 0.0122

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.8
DANN	Benign	0.65
PhyloP100		-0.070

Splicing

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

Other links and lift over

dbSNP: rs8192335; hg19: chr8-22016932;