rs2341009

Variant names:

• chr22-50695152-C-A
• rs2341009
• NM_001372044.2:c.1527+106C>A

Your query was ambiguous. Multiple possible variants found:

• chr22-50695152-C-A
• chr22-50695152-C-G

Variant summary

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

The NM_001372044.2(SHANK3):​c.1527+106C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 1,332,436 control chromosomes in the GnomAD database, including 365,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.76 (43962 hom., cov: 31)
  • Exomes 𝑓: 0.74 (321306 hom.)
• Consequence: SHANK3 NM_001372044.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.68
• Publications: 6 publications found

Genes affected

SHANK3 (HGNC:14294): (SH3 and multiple ankyrin repeat domains 3) This gene is a member of the Shank gene family. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation. Mutations in this gene are a cause of autism spectrum disorder (ASD), which is characterized by impairments in social interaction and communication, and restricted behavioral patterns and interests. Mutations in this gene also cause schizophrenia type 15, and are a major causative factor in the neurological symptoms of 22q13.3 deletion syndrome, which is also known as Phelan-McDermid syndrome. Additional isoforms have been described for this gene but they have not yet been experimentally verified. [provided by RefSeq, Mar 2012]

SHANK3 Gene-Disease associations (from GenCC):

• Phelan-McDermid syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• schizophrenia 15

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 22-50695152-C-A is Benign according to our data. Variant chr22-50695152-C-A is described in ClinVar as Benign. ClinVar VariationId is 1228812.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372044.2. 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
	SHANK3	NM_001372044.2	MANE Select	c.1527+106C>A		intron	N/A	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.1529+104C>A		intron	N/A	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000262795.8	TSL:5	c.947+104C>A		intron	N/A	ENSP00000489147.3	A0A0U1RQS4
	SHANK3	ENST00000414786.8	TSL:5	n.1531+104C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.759 AC: 115331 AN: 151878 Hom.: 43932 Cov.: 31

Gnomad AFR AF: 0.797

Gnomad AMI AF: 0.648

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.780

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.652

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.761

GnomAD4 exome AF: 0.736 AC: 868411 AN: 1180440 Hom.: 321306 AF XY: 0.733 AC XY: 423302 AN XY: 577876

African (AFR) AF: 0.796 AC: 21124 AN: 26530

American (AMR) AF: 0.840 AC: 20328 AN: 24206

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 14786 AN: 18866

East Asian (EAS) AF: 0.715 AC: 24443 AN: 34208

South Asian (SAS) AF: 0.665 AC: 41278 AN: 62046

European-Finnish (FIN) AF: 0.815 AC: 34341 AN: 42132

Middle Eastern (MID) AF: 0.691 AC: 2448 AN: 3544

European-Non Finnish (NFE) AF: 0.732 AC: 672881 AN: 919158

Other (OTH) AF: 0.739 AC: 36782 AN: 49750

GnomAD4 genome AF: 0.759 AC: 115415 AN: 151996 Hom.: 43962 Cov.: 31 AF XY: 0.759 AC XY: 56380 AN XY: 74294

African (AFR) AF: 0.797 AC: 33023 AN: 41416

American (AMR) AF: 0.815 AC: 12459 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.780 AC: 2707 AN: 3472

East Asian (EAS) AF: 0.642 AC: 3304 AN: 5150

South Asian (SAS) AF: 0.652 AC: 3142 AN: 4818

European-Finnish (FIN) AF: 0.800 AC: 8466 AN: 10578

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.734 AC: 49917 AN: 67968

Other (OTH) AF: 0.755 AC: 1589 AN: 2106

Alfa AF: 0.745 Hom.: 53212

Bravo AF: 0.763

Asia WGS AF: 0.656 AC: 2281 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	-0.85
CADD	Benign	0.59
DANN	Benign	0.79
PhyloP100		-1.7
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2341009;

hg19: chr22-51133580;

COSMIC: COSV53182946;

COSMIC: COSV53182946;