rs4240427

Variant names:

• chr9-128203260-A-G
• rs4240427
• NM_012127.3:c.-6+926T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-128203260-A-G
• chr9-128203260-A-C
• chr9-128203260-A-T

Variant summary

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

The NM_012127.3(CIZ1):​c.-6+926T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.944 in 214,822 control chromosomes in the GnomAD database, including 96,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66478 hom., cov: 32)
  • Exomes 𝑓: 0.97 (29781 hom.)
• Consequence: CIZ1 NM_012127.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.350
• Publications: 6 publications found

Genes affected

CIZ1 (HGNC:16744): (CDKN1A interacting zinc finger protein 1) The protein encoded by this gene is a zinc finger DNA binding protein that interacts with CIP1, part of a complex with cyclin E. The encoded protein may regulate the cellular localization of CIP1. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

DNM1 (HGNC:2972): (dynamin 1) This gene encodes a member of the dynamin subfamily of GTP-binding proteins. The encoded protein possesses unique mechanochemical properties used to tubulate and sever membranes, and is involved in clathrin-mediated endocytosis and other vesicular trafficking processes. Actin and other cytoskeletal proteins act as binding partners for the encoded protein, which can also self-assemble leading to stimulation of GTPase activity. More than sixty highly conserved copies of the 3' region of this gene are found elsewhere in the genome, particularly on chromosomes Y and 15. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

DNM1 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 31A

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• developmental and epileptic encephalopathy, 31B

  Inheritance: AR, AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: 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 9-128203260-A-G is Benign according to our data. Variant chr9-128203260-A-G is described in ClinVar as Benign. ClinVar VariationId is 1182484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012127.3. 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
	CIZ1	NM_012127.3		c.-6+926T>C		intron	N/A	NP_036259.2
	CIZ1	NM_001131015.2		c.-6+926T>C		intron	N/A	NP_001124487.1	Q9ULV3-4
	DNM1	NM_004408.4	MANE Select	c.-211A>G		upstream_gene	N/A	NP_004399.2	Q05193-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIZ1	ENST00000634901.1	TSL:5	c.-500-324T>C		intron	N/A	ENSP00000489425.1	Q9ULV3-1
	CIZ1	ENST00000866500.1		c.-6+926T>C		intron	N/A	ENSP00000536559.1
	CIZ1	ENST00000965482.1		c.-6+713T>C		intron	N/A	ENSP00000635541.1

Frequencies

GnomAD3 genomes AF: 0.933 AC: 141643 AN: 151872 Hom.: 66456 Cov.: 32

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.970

Gnomad ASJ AF: 0.922

Gnomad EAS AF: 0.954

Gnomad SAS AF: 0.937

Gnomad FIN AF: 0.983

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.983

Gnomad OTH AF: 0.939

GnomAD4 exome AF: 0.973 AC: 61130 AN: 62836 Hom.: 29781 AF XY: 0.974 AC XY: 32385 AN XY: 33238

African (AFR) AF: 0.801 AC: 1223 AN: 1526

American (AMR) AF: 0.976 AC: 1575 AN: 1614

Ashkenazi Jewish (ASJ) AF: 0.919 AC: 1413 AN: 1538

East Asian (EAS) AF: 0.936 AC: 2268 AN: 2424

South Asian (SAS) AF: 0.950 AC: 688 AN: 724

European-Finnish (FIN) AF: 0.980 AC: 5446 AN: 5556

Middle Eastern (MID) AF: 0.964 AC: 270 AN: 280

European-Non Finnish (NFE) AF: 0.983 AC: 44863 AN: 45634

Other (OTH) AF: 0.956 AC: 3384 AN: 3540

GnomAD4 genome AF: 0.932 AC: 141711 AN: 151986 Hom.: 66478 Cov.: 32 AF XY: 0.933 AC XY: 69325 AN XY: 74318

African (AFR) AF: 0.819 AC: 33994 AN: 41492

American (AMR) AF: 0.970 AC: 14822 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.922 AC: 3200 AN: 3472

East Asian (EAS) AF: 0.955 AC: 4914 AN: 5148

South Asian (SAS) AF: 0.937 AC: 4521 AN: 4824

European-Finnish (FIN) AF: 0.983 AC: 10342 AN: 10518

Middle Eastern (MID) AF: 0.955 AC: 279 AN: 292

European-Non Finnish (NFE) AF: 0.983 AC: 66752 AN: 67940

Other (OTH) AF: 0.940 AC: 1988 AN: 2114

Alfa AF: 0.956 Hom.: 10550

Bravo AF: 0.927

Asia WGS AF: 0.924 AC: 3214 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.2
DANN	Benign	0.37
PhyloP100		-0.35
PromoterAI		-0.074	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4240427; hg19: chr9-130965539;