rs2246943

Variant names:

• chr6-135370378-A-T
• rs2246943
• NM_001134831.2:c.3110-12191T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001134831.2(AHI1):​c.3110-12191T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 152,054 control chromosomes in the GnomAD database, including 22,393 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (22393 hom., cov: 32)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.410
• Publications: 5 publications found

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]

AHI1 Gene-Disease associations (from GenCC):

• Joubert syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Ambry Genetics
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with ocular defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.3110-12191T>A		intron_variant	Intron 23 of 28	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.3110-12191T>A		intron_variant	Intron 23 of 28	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81878 AN: 151936 Hom.: 22386 Cov.: 32

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.668

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.611

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.565

Gnomad OTH AF: 0.557

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.539 AC: 81926 AN: 152054 Hom.: 22393 Cov.: 32 AF XY: 0.542 AC XY: 40293 AN XY: 74336

African (AFR) AF: 0.439 AC: 18216 AN: 41484

American (AMR) AF: 0.583 AC: 8900 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 2121 AN: 3472

East Asian (EAS) AF: 0.633 AC: 3277 AN: 5174

South Asian (SAS) AF: 0.532 AC: 2564 AN: 4816

European-Finnish (FIN) AF: 0.615 AC: 6497 AN: 10562

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.565 AC: 38390 AN: 67962

Other (OTH) AF: 0.551 AC: 1164 AN: 2112

Alfa AF: 0.549 Hom.: 2828

Bravo AF: 0.536

Asia WGS AF: 0.570 AC: 1985 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.0
DANN	Benign	0.64
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism (auto)

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: rs2246943; hg19: chr6-135691516; COSMIC: COSV55625106;