6-135318577-G-C

Variant names:

• chr6-135318577-G-C
• NM_001134831.2:c.3368C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001134831.2(AHI1):​c.3368C>G​(p.Ser1123Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,742 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. 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. S1123F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.18

Genes affected

AHI1 (HGNC:21575): (Abelson helper integration site 1) This gene is apparently required for both cerebellar and cortical development in humans. This gene mutations cause specific forms of Joubert syndrome-related disorders. Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.3368C>G	p.Ser1123Cys	missense_variant	Exon 26 of 29	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.3368C>G	p.Ser1123Cys	missense_variant	Exon 26 of 29	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453742 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.79	.;.;T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.97	L;L;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.79	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.16	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.66
MutPred		0.068		Loss of phosphorylation at S1123 (P = 0.0035);Loss of phosphorylation at S1123 (P = 0.0035);Loss of phosphorylation at S1123 (P = 0.0035);
MVP		0.74
MPC		0.26
ClinPred		0.74	D
GERP RS		5.2
Varity_R		0.12
gMVP		0.25

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-135639715;