chr8-112228859-T-G

Variant names:

• chr8-112228859-T-G
• rs1592624
• NM_198123.2:c.10861A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_198123.2(CSMD3):​c.10861A>C​(p.Asn3621His) variant causes a missense change. The variant allele was found at a frequency of 0.581 in 1,569,996 control chromosomes in the GnomAD database, including 271,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.67 (35641 hom., cov: 33)
  • Exomes 𝑓: 0.57 (235782 hom.)
• Consequence: CSMD3 NM_198123.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.26
• Publications: 30 publications found

Genes affected

CSMD3 (HGNC:19291): (CUB and Sushi multiple domains 3) Predicted to be involved in regulation of dendrite development. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CSMD3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.572054E-7).
• BP6: Variant 8-112228859-T-G is Benign according to our data. Variant chr8-112228859-T-G is described in ClinVar as Benign. ClinVar VariationId is 3060958.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.882 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198123.2. 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
	CSMD3	NM_198123.2	MANE Select	c.10861A>C	p.Asn3621His	missense	Exon 70 of 71	NP_937756.1	Q7Z407-1
	CSMD3	NM_198124.2		c.10741A>C	p.Asn3581His	missense	Exon 71 of 72	NP_937757.1	Q7Z407-2
	CSMD3	NM_052900.3		c.10354A>C	p.Asn3452His	missense	Exon 68 of 69	NP_443132.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSMD3	ENST00000297405.10	TSL:1 MANE Select	c.10861A>C	p.Asn3621His	missense	Exon 70 of 71	ENSP00000297405.5	Q7Z407-1
	CSMD3	ENST00000343508.7	TSL:1	c.10741A>C	p.Asn3581His	missense	Exon 71 of 72	ENSP00000345799.3	Q7Z407-2
	CSMD3	ENST00000455883.2	TSL:1	c.10354A>C	p.Asn3452His	missense	Exon 68 of 69	ENSP00000412263.2	Q7Z407-3

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101397 AN: 151982 Hom.: 35601 Cov.: 33

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.660

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.755

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.696

GnomAD2 exomes AF: 0.612 AC: 153171 AN: 250448 AF XY: 0.604

Gnomad AFR exome AF: 0.900

Gnomad AMR exome AF: 0.609

Gnomad ASJ exome AF: 0.680

Gnomad EAS exome AF: 0.753

Gnomad FIN exome AF: 0.541

Gnomad NFE exome AF: 0.560

Gnomad OTH exome AF: 0.612

GnomAD4 exome AF: 0.571 AC: 809922 AN: 1417896 Hom.: 235782 Cov.: 28 AF XY: 0.571 AC XY: 404546 AN XY: 708038

African (AFR) AF: 0.902 AC: 29071 AN: 32214

American (AMR) AF: 0.607 AC: 27093 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 17476 AN: 25868

East Asian (EAS) AF: 0.736 AC: 28949 AN: 39308

South Asian (SAS) AF: 0.594 AC: 50684 AN: 85278

European-Finnish (FIN) AF: 0.538 AC: 28568 AN: 53092

Middle Eastern (MID) AF: 0.691 AC: 3901 AN: 5646

European-Non Finnish (NFE) AF: 0.548 AC: 588326 AN: 1073062

Other (OTH) AF: 0.610 AC: 35854 AN: 58798

GnomAD4 genome AF: 0.667 AC: 101487 AN: 152100 Hom.: 35641 Cov.: 33 AF XY: 0.661 AC XY: 49126 AN XY: 74326

African (AFR) AF: 0.890 AC: 36970 AN: 41542

American (AMR) AF: 0.611 AC: 9344 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 2384 AN: 3472

East Asian (EAS) AF: 0.755 AC: 3899 AN: 5164

South Asian (SAS) AF: 0.586 AC: 2821 AN: 4816

European-Finnish (FIN) AF: 0.536 AC: 5659 AN: 10554

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.561 AC: 38140 AN: 67954

Other (OTH) AF: 0.692 AC: 1465 AN: 2116

Alfa AF: 0.598 Hom.: 131411

Bravo AF: 0.685

TwinsUK AF: 0.539 AC: 2000

ALSPAC AF: 0.558 AC: 2152

ESP6500AA AF: 0.881 AC: 3881

ESP6500EA AF: 0.559 AC: 4800

ExAC AF: 0.614 AC: 74530

Asia WGS AF: 0.703 AC: 2444 AN: 3472

EpiCase AF: 0.572

EpiControl AF: 0.577

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CSMD3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	8.6e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.092
Sift	Benign	0.18	T
Sift4G	Benign	0.58	T
Polyphen		0.99	D
Vest4		0.23
MPC		0.49
ClinPred		0.045	T
GERP RS		5.6
Varity_R		0.17
gMVP		0.28
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1592624; hg19: chr8-113241088; COSMIC: COSV52174720;