rs200087210

Variant names:

• chr22-50721831-T-G
• rs200087210
• NM_001372044.2:c.4184T>G

Your query was ambiguous. Multiple possible variants found:

• chr22-50721831-T-G
• chr22-50721831-T-A
• chr22-50721831-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001372044.2(SHANK3):​c.4184T>G​(p.Val1395Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000782 in 1,558,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1395V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00079 (0 hom.)
• Consequence: SHANK3 NM_001372044.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.353
• 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, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Laboratory for Molecular Medicine
• schizophrenia 15

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014323235).
• BP6: Variant 22-50721831-T-G is Benign according to our data. Variant chr22-50721831-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 588226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000697 (106/152182) while in subpopulation AMR AF = 0.00131 (20/15304). AF 95% confidence interval is 0.000865. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 106 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.4184T>G	p.Val1395Gly	missense	Exon 24 of 25	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.4181T>G	p.Val1394Gly	missense	Exon 22 of 23	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000262795.8	TSL:5	c.3599T>G	p.Val1200Gly	missense	Exon 20 of 21	ENSP00000489147.3	A0A0U1RQS4
	SHANK3	ENST00000664402.3		c.2141T>G	p.Val714Gly	missense	Exon 5 of 6	ENSP00000499475.2	A0A590UJL3

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 106 AN: 152064 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000564 AC: 91 AN: 161302 AF XY: 0.000507

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000745

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000628

Gnomad NFE exome AF: 0.000983

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000791 AC: 1113 AN: 1406790 Hom.: 0 Cov.: 34 AF XY: 0.000783 AC XY: 544 AN XY: 694780

African (AFR) AF: 0.000125 AC: 4 AN: 31896

American (AMR) AF: 0.000873 AC: 32 AN: 36656

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25224

East Asian (EAS) AF: 0.00 AC: 0 AN: 36268

South Asian (SAS) AF: 0.00 AC: 0 AN: 79942

European-Finnish (FIN) AF: 0.000185 AC: 9 AN: 48584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.000955 AC: 1035 AN: 1084154

Other (OTH) AF: 0.000548 AC: 32 AN: 58356

GnomAD4 genome AF: 0.000697 AC: 106 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.000538 AC XY: 40 AN XY: 74408

African (AFR) AF: 0.000265 AC: 11 AN: 41542

American (AMR) AF: 0.00131 AC: 20 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00104 AC: 71 AN: 67958

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000688

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000249 AC: 2

ExAC AF: 0.000376 AC: 43

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_noAF	Benign	-0.81
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.35
PrimateAI	Uncertain	0.57	T
REVEL	Benign	0.10
Sift4G	Benign	0.38	T
Vest4		0.12
GERP RS		1.2
gMVP		0.44
Mutation Taster		=96/4	polymorphism

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: rs200087210; hg19: chr22-51160259;