12-70335498-A-G
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2
The NM_014515.7(CNOT2):c.710A>G(p.Asn237Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000442 in 1,607,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).
Frequency
Consequence
NM_014515.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CNOT2 | NM_014515.7 | c.710A>G | p.Asn237Ser | missense_variant | Exon 8 of 16 | ENST00000229195.8 | NP_055330.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000256 AC: 39AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000717 AC: 18AN: 251208Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135788
GnomAD4 exome AF: 0.0000220 AC: 32AN: 1455228Hom.: 0 Cov.: 27 AF XY: 0.0000152 AC XY: 11AN XY: 724474
GnomAD4 genome AF: 0.000256 AC: 39AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24AN XY: 74434
ClinVar
Submissions by phenotype
Inborn genetic diseases Benign:1
This alteration is classified as likely 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. -
not provided Benign:1
The CNOT2 p.N237S variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs201309251) and in control databases in 22 of 282610 chromosomes at a frequency of 0.00007785, and was observed at the highest frequency in the African population in 21 of 24946 chromosomes (freq: 0.0008418) (Genome Aggregation Database March 6, 2019, v2.1.1). This frequency is greater than expected for the rare, autosomal dominant intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies condition associated with CNOT2 variants. The p.N237 residue is conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at