rs6914831

Variant names:

• chr6-135318506-C-T
• rs6914831
• ENST00000367799.7:c.2491G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-135318506-C-T
• chr6-135318506-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000367799.7(AHI1):​c.2491G>A​(p.Glu831Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 1,533,058 control chromosomes in the GnomAD database, including 251,668 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26512 hom., cov: 32)
  • Exomes 𝑓: 0.57 (225156 hom.)
• Consequence: AHI1 ENST00000367799.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0760
• Publications: 17 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, Laboratory for Molecular Medicine, ClinGen, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-135318506-C-T is Benign according to our data. Variant chr6-135318506-C-T is described in ClinVar as Benign. ClinVar VariationId is 95757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000367799.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	NM_001134831.2	MANE Select	c.3426+13G>A		intron	N/A	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.3426+13G>A		intron	N/A	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.3426+13G>A		intron	N/A	NP_001337432.1	Q8N157-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000367799.7	TSL:1	c.2491G>A	p.Glu831Lys	missense	Exon 18 of 18	ENSP00000356773.3	H0Y343
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.3426+13G>A		intron	N/A	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.3426+13G>A		intron	N/A	ENSP00000356774.4	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.590 AC: 89578 AN: 151936 Hom.: 26484 Cov.: 32

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.669

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.566

Gnomad OTH AF: 0.601

GnomAD2 exomes AF: 0.588 AC: 107534 AN: 182890 AF XY: 0.583

Gnomad AFR exome AF: 0.616

Gnomad AMR exome AF: 0.644

Gnomad ASJ exome AF: 0.610

Gnomad EAS exome AF: 0.630

Gnomad FIN exome AF: 0.609

Gnomad NFE exome AF: 0.562

Gnomad OTH exome AF: 0.564

GnomAD4 exome AF: 0.569 AC: 786425 AN: 1381004 Hom.: 225156 Cov.: 25 AF XY: 0.569 AC XY: 389817 AN XY: 684864

African (AFR) AF: 0.622 AC: 19865 AN: 31958

American (AMR) AF: 0.640 AC: 24070 AN: 37638

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 15306 AN: 25110

East Asian (EAS) AF: 0.680 AC: 25805 AN: 37930

South Asian (SAS) AF: 0.552 AC: 43995 AN: 79696

European-Finnish (FIN) AF: 0.597 AC: 30258 AN: 50658

Middle Eastern (MID) AF: 0.634 AC: 3579 AN: 5648

European-Non Finnish (NFE) AF: 0.560 AC: 590469 AN: 1054892

Other (OTH) AF: 0.576 AC: 33078 AN: 57474

GnomAD4 genome AF: 0.590 AC: 89662 AN: 152054 Hom.: 26512 Cov.: 32 AF XY: 0.592 AC XY: 44005 AN XY: 74346

African (AFR) AF: 0.613 AC: 25423 AN: 41446

American (AMR) AF: 0.606 AC: 9266 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2115 AN: 3470

East Asian (EAS) AF: 0.620 AC: 3209 AN: 5174

South Asian (SAS) AF: 0.532 AC: 2562 AN: 4818

European-Finnish (FIN) AF: 0.620 AC: 6554 AN: 10570

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

European-Non Finnish (NFE) AF: 0.566 AC: 38469 AN: 67978

Other (OTH) AF: 0.599 AC: 1265 AN: 2112

Alfa AF: 0.578 Hom.: 45950

Bravo AF: 0.594

Asia WGS AF: 0.586 AC: 2040 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Joubert syndrome 3 (3)
-	-	1	Joubert syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.0
DANN	Benign	0.30
PhyloP100		0.076
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: rs6914831; hg19: chr6-135639644; COSMIC: COSV55628835;