8-22161852-C-G

Variant names:

• chr8-22161852-C-G
• rs144603526
• NM_001317778.2:c.24C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001317778.2(SFTPC):​c.24C>G​(p.Val8Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000886 in 1,614,032 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (10 hom.)
• Consequence: SFTPC NM_001317778.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0580
• 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, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 8-22161852-C-G is Benign according to our data. Variant chr8-22161852-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 362550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.058 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000795 (121/152252) while in subpopulation AMR AF = 0.000392 (6/15296). AF 95% confidence interval is 0.000267. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 121 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317778.2. 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_001317778.2	MANE Select	c.24C>G	p.Val8Val	synonymous	Exon 1 of 6	NP_001304707.1	P11686-2
	SFTPC	NM_001172410.2		c.24C>G	p.Val8Val	synonymous	Exon 1 of 6	NP_001165881.1	A0A0S2Z4Q0
	SFTPC	NM_001385653.1		c.24C>G	p.Val8Val	synonymous	Exon 1 of 6	NP_001372582.1	P11686-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPC	ENST00000679463.1	MANE Select	c.24C>G	p.Val8Val	synonymous	Exon 1 of 6	ENSP00000505152.1	P11686-2
	SFTPC	ENST00000318561.7	TSL:1	c.24C>G	p.Val8Val	synonymous	Exon 1 of 6	ENSP00000316152.3	P11686-1
	SFTPC	ENST00000521315.5	TSL:1	c.24C>G	p.Val8Val	synonymous	Exon 1 of 5	ENSP00000430410.1	P11686-2

Frequencies

GnomAD3 genomes AF: 0.000795 AC: 121 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00152 AC: 380 AN: 249316 AF XY: 0.00162

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.0287

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000619

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000895 AC: 1309 AN: 1461780 Hom.: 10 Cov.: 32 AF XY: 0.000909 AC XY: 661 AN XY: 727180

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 728 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53324

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000405 AC: 450 AN: 1111998

Other (OTH) AF: 0.00185 AC: 112 AN: 60394

GnomAD4 genome AF: 0.000795 AC: 121 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000672 AC XY: 50 AN XY: 74444

African (AFR) AF: 0.0000963 AC: 4 AN: 41552

American (AMR) AF: 0.000392 AC: 6 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68006

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00534 Hom.: 3

Bravo AF: 0.000971

EpiCase AF: 0.00125

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Surfactant metabolism dysfunction, pulmonary, 2 (2)
-	-	1	Hereditary pulmonary alveolar proteinosis (1)
-	-	1	Interstitial lung disease 2 (1)
-	-	1	Pulmonary Surfactant Metabolism Dysfunction, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	9.8
DANN	Benign	0.83
PhyloP100		-0.058
PromoterAI		-0.026	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144603526; hg19: chr8-22019365;