chr11-70473268-C-T

Variant names:

• chr11-70473268-C-T
• rs140134890
• NM_012309.5:c.5151G>A

Variant summary

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

The NM_001441024.1(SHANK2):​c.5271G>A​(p.Met1757Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,612,480 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (16 hom.)
• Consequence: SHANK2 NM_001441024.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.428
• Publications: 11 publications found

Genes affected

SHANK2 (HGNC:14295): (SH3 and multiple ankyrin repeat domains 2) This gene encodes a protein that is a member of the Shank family of synaptic proteins that may function as molecular scaffolds in the postsynaptic density of excitatory synapses. Shank proteins contain multiple domains for protein-protein interaction, including ankyrin repeats, and an SH3 domain. This particular family member contains a PDZ domain, a consensus sequence for cortactin SH3 domain-binding peptides and a sterile alpha motif. The alternative splicing demonstrated in Shank genes has been suggested as a mechanism for regulating the molecular structure of Shank and the spectrum of Shank-interacting proteins in the postsynaptic densities of the adult and developing brain. Alterations in the encoded protein may be associated with susceptibility to autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

SHANK2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autism, susceptibility to, 17

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024030209).
• BP6: Variant 11-70473268-C-T is Benign according to our data. Variant chr11-70473268-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00267 (407/152202) while in subpopulation NFE AF = 0.00321 (218/68014). AF 95% confidence interval is 0.00286. There are 4 homozygotes in GnomAd4. There are 216 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 407 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001441024.1. 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
	SHANK2	NM_012309.5	MANE Select	c.5151G>A	p.Met1717Ile	missense	Exon 26 of 26	NP_036441.2
	SHANK2	NM_001441024.1		c.5271G>A	p.Met1757Ile	missense	Exon 24 of 24	NP_001427953.1
	SHANK2	NM_001441025.1		c.5100G>A	p.Met1700Ile	missense	Exon 23 of 23	NP_001427954.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK2	ENST00000601538.6	TSL:5 MANE Select	c.5151G>A	p.Met1717Ile	missense	Exon 26 of 26	ENSP00000469689.2
	SHANK2	ENST00000409161.5	TSL:1	c.3363G>A	p.Met1121Ile	missense	Exon 10 of 10	ENSP00000386491.1
	SHANK2	ENST00000916035.1		c.5100G>A	p.Met1700Ile	missense	Exon 23 of 23	ENSP00000586094.1

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 407 AN: 152084 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00320

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00293 AC: 735 AN: 250802 AF XY: 0.00300

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.00267

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00178 AC: 2601 AN: 1460278 Hom.: 16 Cov.: 32 AF XY: 0.00190 AC XY: 1377 AN XY: 726104

African (AFR) AF: 0.0000598 AC: 2 AN: 33450

American (AMR) AF: 0.000201 AC: 9 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86228

European-Finnish (FIN) AF: 0.0174 AC: 930 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00140 AC: 1560 AN: 1110686

Other (OTH) AF: 0.00159 AC: 96 AN: 60322

GnomAD4 genome AF: 0.00267 AC: 407 AN: 152202 Hom.: 4 Cov.: 33 AF XY: 0.00290 AC XY: 216 AN XY: 74400

African (AFR) AF: 0.0000963 AC: 4 AN: 41536

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.0161 AC: 170 AN: 10586

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

European-Non Finnish (NFE) AF: 0.00321 AC: 218 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00226 Hom.: 4

Bravo AF: 0.00125

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00210 AC: 18

ExAC AF: 0.00279 AC: 339

EpiCase AF: 0.00213

EpiControl AF: 0.00130

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.4
DANN	Benign	0.94
DEOGEN2	Benign	0.0079	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.43
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.062
Sift	Benign	0.42	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.045
MVP		0.19
MPC		0.51
ClinPred		0.0075	T
GERP RS		0.46
gMVP		0.11
Mutation Taster		=99/1	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: rs140134890; hg19: chr11-70319373; COSMIC: COSV53620965; COSMIC: COSV53620965;