2-96129869-T-G

Variant names:

• chr2-96129869-T-G
• rs1657502
• NM_001002036.4:c.829A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001002036.4(ASTL):​c.829A>C​(p.Lys277Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,594,978 control chromosomes in the GnomAD database, including 114,785 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.36 (10521 hom., cov: 32)
  • Exomes 𝑓: 0.37 (104264 hom.)
• Consequence: ASTL NM_001002036.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.866
• Publications: 33 publications found

Genes affected

ASTL (HGNC:31704): (astacin like metalloendopeptidase) Predicted to enable aspartic-type peptidase activity; glutamic-type peptidase activity; and metalloendopeptidase activity. Predicted to be involved in several processes, including negative regulation of binding activity of sperm to zona pellucida; positive regulation of protein processing; and prevention of polyspermy. Predicted to be located in cortical granule and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5303493E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002036.4. 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
	ASTL	NM_001002036.4	MANE Select	c.829A>C	p.Lys277Gln	missense	Exon 8 of 9	NP_001002036.3	Q6HA08

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASTL	ENST00000342380.3	TSL:1 MANE Select	c.829A>C	p.Lys277Gln	missense	Exon 8 of 9	ENSP00000343674.2	Q6HA08
	ASTL	ENST00000867255.1		c.775A>C	p.Lys259Gln	missense	Exon 8 of 9	ENSP00000537314.1

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54879 AN: 151938 Hom.: 10506 Cov.: 32

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.320

GnomAD2 exomes AF: 0.393 AC: 96751 AN: 246106 AF XY: 0.380

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.509

Gnomad ASJ exome AF: 0.240

Gnomad EAS exome AF: 0.628

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.367

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.374 AC: 539292 AN: 1442922 Hom.: 104264 Cov.: 37 AF XY: 0.368 AC XY: 263155 AN XY: 714572

African (AFR) AF: 0.285 AC: 9425 AN: 33042

American (AMR) AF: 0.499 AC: 21833 AN: 43752

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 6152 AN: 25600

East Asian (EAS) AF: 0.575 AC: 22579 AN: 39274

South Asian (SAS) AF: 0.264 AC: 22381 AN: 84886

European-Finnish (FIN) AF: 0.488 AC: 25943 AN: 53130

Middle Eastern (MID) AF: 0.185 AC: 865 AN: 4680

European-Non Finnish (NFE) AF: 0.372 AC: 409262 AN: 1099224

Other (OTH) AF: 0.351 AC: 20852 AN: 59334

GnomAD4 genome AF: 0.361 AC: 54944 AN: 152056 Hom.: 10521 Cov.: 32 AF XY: 0.366 AC XY: 27207 AN XY: 74316

African (AFR) AF: 0.297 AC: 12301 AN: 41456

American (AMR) AF: 0.402 AC: 6147 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 824 AN: 3470

East Asian (EAS) AF: 0.612 AC: 3157 AN: 5162

South Asian (SAS) AF: 0.270 AC: 1301 AN: 4820

European-Finnish (FIN) AF: 0.492 AC: 5206 AN: 10584

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.365 AC: 24839 AN: 67960

Other (OTH) AF: 0.319 AC: 673 AN: 2110

Alfa AF: 0.361 Hom.: 33972

Bravo AF: 0.360

TwinsUK AF: 0.365 AC: 1355

ALSPAC AF: 0.371 AC: 1431

ESP6500AA AF: 0.294 AC: 1297

ESP6500EA AF: 0.362 AC: 3115

ExAC AF: 0.383 AC: 46466

Asia WGS AF: 0.383 AC: 1331 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.00015	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.52	N
PhyloP100		0.87
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Benign	0.079	T
Sift4G	Benign	0.32	T
Polyphen		0.026	B
Vest4		0.049
MPC		0.18
ClinPred		0.0070	T
GERP RS		-2.3
Varity_R		0.26
gMVP		0.57
Mutation Taster		=96/4	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

Other links and lift over

dbSNP: rs1657502; hg19: chr2-96795608; COSMIC: COSV60904250; COSMIC: COSV60904250;