rs2757639

Variant names:

• chr6-135427062-A-G
• rs2757639
• NM_001134831.2:c.2764+105T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-135427062-A-G
• chr6-135427062-A-C
• chr6-135427062-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001134831.2(AHI1):​c.2764+105T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.929 in 1,153,620 control chromosomes in the GnomAD database, including 498,956 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.88 (59966 hom., cov: 32)
  • Exomes 𝑓: 0.94 (438990 hom.)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00200
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-135427062-A-G is Benign according to our data. Variant chr6-135427062-A-G is described in ClinVar as Benign. ClinVar VariationId is 1247098.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134831.2. 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.2764+105T>C		intron	N/A	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.2764+105T>C		intron	N/A	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.2764+105T>C		intron	N/A	NP_001337432.1	Q8N157-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.2764+105T>C		intron	N/A	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.2764+105T>C		intron	N/A	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.2764+105T>C		intron	N/A	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.885 AC: 134094 AN: 151514 Hom.: 59938 Cov.: 32

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.967

Gnomad AMR AF: 0.923

Gnomad ASJ AF: 0.979

Gnomad EAS AF: 0.966

Gnomad SAS AF: 0.948

Gnomad FIN AF: 0.976

Gnomad MID AF: 0.956

Gnomad NFE AF: 0.935

Gnomad OTH AF: 0.898

GnomAD4 exome AF: 0.935 AC: 937264 AN: 1001988 Hom.: 438990 AF XY: 0.937 AC XY: 474771 AN XY: 506816

African (AFR) AF: 0.744 AC: 16236 AN: 21826

American (AMR) AF: 0.931 AC: 22329 AN: 23992

Ashkenazi Jewish (ASJ) AF: 0.978 AC: 21069 AN: 21540

East Asian (EAS) AF: 0.968 AC: 32271 AN: 33354

South Asian (SAS) AF: 0.949 AC: 58148 AN: 61258

European-Finnish (FIN) AF: 0.970 AC: 42406 AN: 43704

Middle Eastern (MID) AF: 0.962 AC: 3131 AN: 3254

European-Non Finnish (NFE) AF: 0.936 AC: 700219 AN: 748464

Other (OTH) AF: 0.930 AC: 41455 AN: 44596

GnomAD4 genome AF: 0.885 AC: 134176 AN: 151632 Hom.: 59966 Cov.: 32 AF XY: 0.888 AC XY: 65889 AN XY: 74172

African (AFR) AF: 0.738 AC: 30572 AN: 41434

American (AMR) AF: 0.923 AC: 14046 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.979 AC: 3390 AN: 3462

East Asian (EAS) AF: 0.966 AC: 5002 AN: 5180

South Asian (SAS) AF: 0.948 AC: 4575 AN: 4828

European-Finnish (FIN) AF: 0.976 AC: 10367 AN: 10618

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.935 AC: 63175 AN: 67586

Other (OTH) AF: 0.897 AC: 1887 AN: 2104

Alfa AF: 0.895 Hom.: 13892

Bravo AF: 0.876

Asia WGS AF: 0.914 AC: 3179 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.61
PhyloP100		-0.0020
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: rs2757639; hg19: chr6-135748200;