22-50675029-C-G

Variant names:

• chr22-50675029-C-G
• rs757516415
• NM_001372044.2:c.289-19C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001372044.2(SHANK3):​c.289-19C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000651 in 1,524,478 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00055 (8 hom.)
• Consequence: SHANK3 NM_001372044.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.934
• Publications: 0 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: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• schizophrenia 15

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

ENSG00000301328 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-50675029-C-G is Benign according to our data. Variant chr22-50675029-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1253739.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00155 (235/151132) while in subpopulation NFE AF = 0.000489 (33/67506). AF 95% confidence interval is 0.000358. There are 1 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 235 AD gene.

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.289-19C>G		intron	N/A	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.289-19C>G		intron	N/A	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000262795.8	TSL:5	c.-313C>G		5_prime_UTR	Exon 1 of 21	ENSP00000489147.3	A0A0U1RQS4
	SHANK3	ENST00000691768.1		n.8C>G		non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 235 AN: 151018 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000489

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000975 AC: 122 AN: 125174 AF XY: 0.000990

Gnomad AFR exome AF: 0.000173

Gnomad AMR exome AF: 0.0000833

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.000262

Gnomad OTH exome AF: 0.000260

GnomAD4 exome AF: 0.000552 AC: 758 AN: 1373346 Hom.: 8 Cov.: 31 AF XY: 0.000534 AC XY: 361 AN XY: 676430

African (AFR) AF: 0.0000323 AC: 1 AN: 31004

American (AMR) AF: 0.0000568 AC: 2 AN: 35236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24722

East Asian (EAS) AF: 0.00 AC: 0 AN: 35274

South Asian (SAS) AF: 0.000511 AC: 40 AN: 78204

European-Finnish (FIN) AF: 0.0131 AC: 468 AN: 35648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4022

European-Non Finnish (NFE) AF: 0.000204 AC: 219 AN: 1072150

Other (OTH) AF: 0.000490 AC: 28 AN: 57086

GnomAD4 genome AF: 0.00155 AC: 235 AN: 151132 Hom.: 1 Cov.: 31 AF XY: 0.00242 AC XY: 179 AN XY: 73818

African (AFR) AF: 0.0000242 AC: 1 AN: 41290

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5058

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4800

European-Finnish (FIN) AF: 0.0188 AC: 197 AN: 10486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000489 AC: 33 AN: 67506

Other (OTH) AF: 0.00143 AC: 3 AN: 2102

Alfa AF: 0.000546 Hom.: 0

Bravo AF: 0.000181

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	-0.80
CADD	Benign	8.2
DANN	Benign	0.56
PhyloP100		-0.93
PromoterAI		-0.033	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: 19

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

Other links and lift over

dbSNP: rs757516415; hg19: chr22-51113457;