rs121917834

Variant names:

• chr8-22163096-T-A
• rs121917834
• NM_001317778.2:c.218T>A

Your query was ambiguous. Multiple possible variants found:

• chr8-22163096-T-A
• chr8-22163096-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM5 BS2

The NM_001317778.2(SFTPC):​c.218T>A​(p.Ile73Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I73T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SFTPC NM_001317778.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22
• Publications: 120 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: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001317778.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-22163096-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPC	NM_001317778.2	c.218T>A	p.Ile73Asn	missense_variant	Exon 3 of 6	ENST00000679463.1	NP_001304707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPC	ENST00000679463.1	c.218T>A	p.Ile73Asn	missense_variant	Exon 3 of 6		NM_001317778.2	ENSP00000505152.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000361 AC: 9 AN: 249478 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000501

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461846 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111996

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000331 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T;T;.;D;D;T;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
PhyloP100		2.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.6	D;N;D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		0.97, 0.90	.;.;D;.;P;.;.
Vest4		0.67
MutPred		0.70		Gain of disorder (P = 0.0051);Gain of disorder (P = 0.0051);Gain of disorder (P = 0.0051);.;Gain of disorder (P = 0.0051);.;.;
MVP		1.0
MPC		1.7
ClinPred		0.46	T
GERP RS		4.7
gMVP		0.92
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs121917834; hg19: chr8-22020609;