NM_003002.4:c.312C>T
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_003002.4(SDHD):c.312C>T(p.His104His) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,152 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_003002.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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SDHD | NM_003002.4 | c.312C>T | p.His104His | splice_region_variant, synonymous_variant | Exon 3 of 4 | ENST00000375549.8 | NP_002993.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHD | ENST00000375549.8 | c.312C>T | p.His104His | splice_region_variant, synonymous_variant | Exon 3 of 4 | 1 | NM_003002.4 | ENSP00000364699.3 | ||
ENSG00000255292 | ENST00000532699.1 | n.312C>T | splice_region_variant, non_coding_transcript_exon_variant | Exon 3 of 6 | 3 | ENSP00000456434.1 |
Frequencies
GnomAD3 genomes AF: 0.00637 AC: 970AN: 152184Hom.: 7 Cov.: 32
GnomAD3 exomes AF: 0.00178 AC: 447AN: 251478Hom.: 3 AF XY: 0.00142 AC XY: 193AN XY: 135918
GnomAD4 exome AF: 0.000644 AC: 942AN: 1461850Hom.: 5 Cov.: 31 AF XY: 0.000584 AC XY: 425AN XY: 727230
GnomAD4 genome AF: 0.00636 AC: 969AN: 152302Hom.: 7 Cov.: 32 AF XY: 0.00603 AC XY: 449AN XY: 74476
ClinVar
Submissions by phenotype
not specified Benign:4
Classification criteria: BA1 -
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not provided Benign:3
Variant summary: The SDHD c.312C>T (p.His104His) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 260/121396 control chromosomes (including 3 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0238599 (248/10394). This frequency greatly exceeds the estimated maximal expected allele frequency of a pathogenic SDHD variant (0.0000016), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories have classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
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Paragangliomas 1 Benign:2
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Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Benign:1
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Pheochromocytoma Benign:1
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Paragangliomas 3 Benign:1
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Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C3494181:Paragangliomas 1;C5436934:Mitochondrial complex 2 deficiency, nuclear type 3 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at