14-94304471-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_001756.4(SERPINA6):c.1165G>A(p.Asp389Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000358 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001756.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SERPINA6 | NM_001756.4 | c.1165G>A | p.Asp389Asn | missense_variant | Exon 5 of 5 | ENST00000341584.4 | NP_001747.3 | |
SERPINA6 | XM_047431827.1 | c.1336G>A | p.Asp446Asn | missense_variant | Exon 5 of 5 | XP_047287783.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SERPINA6 | ENST00000341584.4 | c.1165G>A | p.Asp389Asn | missense_variant | Exon 5 of 5 | 1 | NM_001756.4 | ENSP00000342850.3 | ||
SERPINA6 | ENST00000555056.1 | n.*477G>A | non_coding_transcript_exon_variant | Exon 5 of 5 | 2 | ENSP00000451045.1 | ||||
SERPINA6 | ENST00000555056.1 | n.*477G>A | 3_prime_UTR_variant | Exon 5 of 5 | 2 | ENSP00000451045.1 |
Frequencies
GnomAD3 genomes AF: 0.000507 AC: 77AN: 152000Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000617 AC: 155AN: 251322Hom.: 0 AF XY: 0.000567 AC XY: 77AN XY: 135852
GnomAD4 exome AF: 0.000343 AC: 501AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.000355 AC XY: 258AN XY: 727248
GnomAD4 genome AF: 0.000506 AC: 77AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35AN XY: 74368
ClinVar
Submissions by phenotype
Corticosteroid-binding globulin deficiency Pathogenic:4Uncertain:2
- -
- -
NM_001756.3:c.1165G>A in the SERPINA6 gene has an allele frequency of 0.007 in Ashkenazi Jewish subpopulation in the gnomAD database. It was detected in individual with autosomal recessive Corticosteroid-binding globulin deficiency, two homozygous c.1165G>A(PMID: 12780753; 20610591). Co-segregation evidence in a pedigree, two patients were affected and one sibling unaffected (PMID: 20610591). Pathogenic computational verdict because 9 pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster and REVEL. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PP1_Moderate; PM3; PP4; PP3. -
- -
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
- -
SERPINA6-related disorder Pathogenic:1
The SERPINA6 c.1165G>A variant is predicted to result in the amino acid substitution p.Asp389Asn. This variant, also referred to as CBG Lyon or p.Asp367Asn, has been reported in the heterozygous and homozygous state in individuals with corticosteroid-binding globulin (CBG) deficiency (Emptoz-Bonneton et al. 2000. PubMed ID: 10634411; Brunner et al. 2003. PubMed ID: 12780753; Cizza et al. 2011. PubMed ID: 21795453). Functional studies found this variant resulted in reduced affinity for cortisol and results in low or low-normal serum cortisol levels in homozygous and heterozygous subjects (Emptoz-Bonneton et al. 2000. PubMed ID: 10634411; Brunner et al. 2003. PubMed ID: 12780753; Cizza et al. 2011. PubMed ID: 21795453). This variant is reported in 0.77% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. In ClinVar this variant has conflicting interpretations of pathogenicity of uncertain, likely pathogenic, and pathogenic (https://ncbi.nlm.nih.gov/clinvar/variation/16975/). This variant is interpreted as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at